Macrocyclization reactions and intermediates useful in the synthesis of analogs of halichondrin b

ABSTRACT

The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Homer-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compounds useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for preparing the same.

BACKGROUND

The invention relates to intermediates useful in the synthesis of pharmaceutically active macrolide compounds and methods of synthesizing macrolide compounds. Halichondrin B is a potent anticancer agent originally isolated from the marine sponge Halichondria okadai, and subsequently found in Axinella sp., Phakellia carteri, and Lissodendoryx sp. A total synthesis of halichondrin B was published in 1992 (Aicher, T. D. et al., J. Am. Chem. Soc. 114:3162-3164). Eribulin mesylate (also called Halaven®, E7389, and the mesylate salt of B1939), a nontaxane microtubule dynamics inhibitor, is a structurally simplified, synthetic analogue of halichondrin B. Methods and intermediates for the synthesis of eribulin mesylate and other halichondrin B analogues are described in International Publication Nos. WO 2005/118565, WO 2009/046308, WO 2009/064029, and WO 2009/124237; U.S. Pat. No. 6,214,865; Austad et al., Synlett 24(3):333-337, 2013; Austad et al., Synlett. 24(3):327-332, 2013; and Chase et al., Synlett 24(3):323-326, 2013; each of which is hereby incorporated by reference in its entirety. New methods for the synthesis of halichondrin B analogs, in particular eribulin, are desirable.

SUMMARY OF THE INVENTION

In general, the present invention provides methods for macrocyclization of intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate). The invention also provides intermediates that can be employed in the macrocyclization reactions described herein.

In a first aspect, the invention provides a method of preparing an intermediate in the synthesis of eribulin, the method including performing a macrocyclization reaction on a non-macrocyclic intermediate, the macrocyclization reaction producing the intermediate in the synthesis of eribulin by forming a C.15-C.16, C.2-C.3, C.3-C.4, C.19-C.20, C.0-C.1, or C.26-C.27 bond in the structure of eribulin.

In some embodiments of the first aspect, performing the macrocyclization reaction can involve contacting the non-macrocyclic intermediate (e.g., a compound of formula (IA)) with an olefin metathesis catalyst (e.g., a ruthenium-carbene complex). The non-macrocyclic intermediate can be a compound of formula (IA) or a salt thereof:

-   -   where     -   R₁ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₉)₂—, or NP₅, and         where each R₉ is independently H or —COOR₁₀, P₅ is an         N-protecting group, and R₁₀ is C₁₋₆ alkyl;     -   (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl         ether, and R₄ is H;     -   (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄         combine to form a double bond;     -   or     -   (a3) R₂ and R₃ combine to form a bond, and R₄ is H;     -   (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇         combine to form a double bond;     -   or     -   (b2) R₅ and R₆ combine to form a bond, and R₇ is H;     -   (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group;     -   or     -   (c2) R₈ and P₄ combine to form a double bond;     -   each P₃ is independently H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl; and     -   where the intermediate in the synthesis of eribulin can be a         compound of formula (IB) or a salt thereof:

In formula (IA) or (IB), each P₃ and P₄ can be independently a hydroxyl protecting group (e.g., a silyl). In formula (IA) or (IB), P₁ can be a hydroxyl protecting group (e.g., a silyl). In formula (IA) or (IB), X can be O. In formula (IA) or (IB), P₂ is a hydroxyl protecting group (e.g., a silyl). In formula (IA) or (IB), X can be N, and P₁ and P₂, together with the atoms to which each is attached, can combine to form an aminal. In formula (IA) or (IB), R₂ and R₃ can combine to form a bond, and R₄ can be H. In formula (IA) or (IB), R₅ and R₆ can combine to form a bond, and R₇ can be H. In formula (IA) or (IB), R₈ can be H, and P₄ can be a hydroxyl protecting group (e.g., a silyl).

In particular embodiments of the first aspect, performing the macrocyclization reaction involves reacting the non-macrocyclic intermediate (e.g., a compound of formula (IIA)) with an organic base (e.g., an organic base having a pKa of 11±2 (e.g., DBU or trialkylamine (e.g., triethylamine))) and a Lewis acid (e.g., a salt of Li, Mg, or Zn (e.g., lithium chloride or zinc trifluoromethanesulfonate)). In particular, the method can involve performing a Horner-Wadsworth-Emmons reaction on the compound of formula (IIA) to afford the compound of formula (IIB). The non-macrocyclic intermediate can be a compound of formula (IIA) or a salt thereof:

-   -   where     -   each R is independently optionally substituted alkyl or         optionally substituted aryl;     -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃         combine to form a double bond;     -   or     -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   P₄ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl; and     -   where the intermediate in the synthesis of eribulin can be a         compound of formula (IIB) or a salt thereof:

In formula (IIA), each R can be optionally substituted alkyl. In formula (IIA) or (IIB), P₁ can be a hydroxyl protecting group (e.g., a silyl). In formula (IIA) or (IIB), P₂ can be a hydroxyl protecting group (e.g., a silyl). In formula (IIA) or (IIB), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal. In formula (IIA) or (IIB), R₁ and R₂ can form a bond, and R₃ can be H. In formula (IIA) or (IIB), P₄ can be a hydroxyl protecting group (e.g., a silyl).

In some embodiments of the first aspect, performing the macrocyclization reaction involves contacting the non-macrocyclic intermediate (e.g., a compound of formula (IIIA)) with an olefin metathesis catalyst (e.g., a ruthenium-carbene complex). The non-macrocyclic intermediate can be a compound of formula (IIIA) or a salt thereof:

-   -   where     -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃         combine to form a double bond;     -   or     -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;     -   X₃ is oxo, or X₃ combine with the carbon atom to which it is         attached to form a ketal, a thioketal, or —(CH(OP₅))—, where P₅         is H or a hydroxyl protecting group;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   P₄ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl; and     -   where the intermediate in the synthesis of eribulin can be a         compound of formula (IIIB) or a salt thereof:

In formula (IIIA) or (IIIB), P₄ can be a hydroxyl protecting group (e.g., a silyl). In formula (IIIA) or (IIIB), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal. In formula (IIIA) or (IIIB), R₁ and R₂ can form a bond, and R₃ can be H. In formula (IIIA) or (IIIB), X₃ can combine with the carbon atom to which it is attached to form —(CH(OP₅))—. In particular, in formula (IIIA) or (IIIB), P₅ can be H. In formula (IIIA) or (IIIB), P₁ can be a hydroxyl protecting group (e.g., silyl). In formula (IIIA) or (IIIB), P₂ can be a hydroxyl protecting group.

In certain embodiments of the first aspect, performing the macrocyclization reaction includes contacting the non-macrocyclic intermediate (e.g., a compound of formula (IVA)) with a Cr(II) salt and a Ni(II) salt. In particular, the method can involve subjecting a compound of formula (IVA) to Nozaki-Hiyama-Kishi reaction conditions. The non-macrocyclic intermediate can be a compound of formula (IVA) or a salt thereof:

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   a can designate R stereogenic center, and Z is a sulfonate,         chloride, bromide, or iodide; or a can designate S stereogenic         center, and Z is OR₁, where R₁ is a hydroxyl protecting group;     -   R₂ is H or a hydroxyl protecting group, and R₃ and R₄ combine to         form a double bond;     -   or     -   (ii) R₂ and R₃ combine to form a bond, and R₄ is H;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl; and     -   where the intermediate in the synthesis of eribulin can be a         compound of formula (IVB) or a salt thereof:

-   -   where         -   a designates R stereogenic center, b designates S             stereogenic center, and Z is a sulfonate, chloride, bromide,             or iodide;             -   or             -   a designates S stereogenic center, b designates R                 stereogenic center, and Z is OR₁, where R₁ is a hydroxyl                 protecting group.

In formula (IVA) or (IVB), Y can be bromide. In formula (IVA) or (IVB), R₂ and R₃ can combine to form a bond, and R₄ can be H. In formula (IVA) or (IVB), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal. In formula (IVA) or (IVB), P₁ can be a hydroxyl protecting group (e.g., a silyl). In formula (IVA) or (IVB), P₂ can be a hydroxyl protecting group (e.g., a silyl). In formula (IVA) or (IVB), Z can be a sulfonate. In formula (IVA) or (IVB), Z can be OR₁, where R₁ can be a hydroxyl protecting group (e.g., Z can be an ester, carbonate, or carbamate (e.g., Z can be an ester)).

In some embodiments of the first aspect, performing the macrocyclization reaction involves contacting the non-macrocyclic intermediate (e.g., a compound of formula (VA)) with a base (e.g., a tertiary C₄₋₆ alkoxide (e.g., an alkali tertiary C₄₋₆ alkoxide)). In particular, the method can involve subjecting a compound of formula (VA) to the Dieckmann reaction conditions. The non-macrocyclic intermediate can be a compound of formula (VA) or a salt thereof:

-   -   where     -   Y is SO₂R₁, or COOR₁, where, when Y is SO₂R₁, R₁ is optionally         substituted aryl or optionally substituted non-enolizable alkyl,         and when Y is COOR₁, R₁ is optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo, or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   R₂ is optionally substituted alkyl, optionally substituted         arylalkyl, or optionally substituted aryl; and     -   X is O, and         -   each of P₁ and P₂ is independently a hydroxyl protecting             group,         -   or         -   P₁ and P₂, together with the atoms to which each is             attached, combine to form a cyclic protected diol;     -   or     -   X is N, and         -   P₁ is H or a hydroxyl protecting group, and X and P₂ combine             to form optionally masked amino;         -   or         -   P₁ and P₂, together with the atoms to which each is             attached, combine to form an aminal or             1,3-oxazolidin-2-one-5-yl; and     -   where the intermediate in the synthesis of eribulin can be a         compound of formula (VB) or a salt thereof:

-   -   where     -   (i) R₃ is H, R₄ is optionally substituted C₁₋₆ alkyl ether, and         R₅ is H;     -   (ii) R₅ is H, and R₃ and R₄ combine to form a double bond;     -   or     -   (iii) R₃ is H, and R₄ and R₅ combine to form a bond.

In formula (VA) or (VB), Y can be SO₂R₁, (e.g., R₁ can be optionally substituted aryl). In formula (VA) or (VB), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal. In formula (VA) or (VB), R₂ can be optionally substituted alkyl (e.g., unsubstituted C₁₋₆ alkyl). In formula (VA) or (VB), R₃ can be H, and R₄ and R₅ can combine to form a bond.

In other embodiments of the first aspect, performing the macrocyclization reaction includes contacting the non-macrocyclic intermediate (e.g., a compound of formula (VIA)) with a Cr(II) salt and a Ni(II) salt. In particular, the method can involve subjecting a compound of formula (VIA) to Nozaki-Hiyama-Kishi reaction conditions. The non-macrocyclic intermediate can be a compound of formula (VIA) or a salt thereof:

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine         to form a double bond, each P₃ is independently H or a hydroxyl         protecting group, and X₂, together with the carbon to which it         is attached, form a carbonyl or —(CH(OR₆))—, where R₆ is H or a         hydroxyl protecting group;     -   or     -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and         -   each P₃ is independently H or a hydroxyl protecting group,             and X₂, together with the carbon to which it is attached,             form a carbonyl or —(CH(OR₆))—;         -   or         -   both P₃ groups and X₂, together with the atoms to which each             is attached, combine to form ketal;     -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to         form a bond;     -   or     -   (b2) Z and R₂ combine to form a double bond, and R₁ is a         hydroxyl protecting group;     -   and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl; and     -   where the intermediate in the synthesis of eribulin is a         compound of formula (VIB) or a salt thereof:

-   -   where P₄ is H or a hydroxyl protecting group.

In formula (VIA), Z can be iodide, and R₁ and R₂ can combine to form a bond. In formula (VIA), Y can be trifluoromethanesulfonate. In formula (VIA) or (VIB), R₁ can be H, or O and R₁ can combine to form a sulfonate. In formula (VIA) or (VIB), P₁ can be a hydroxyl protecting group (e.g., a silyl). In formula (VIA) or (VIB), P₂ can be a hydroxyl protecting group (e.g., a silyl). In formula (VIA) or (VIB), R₃ can be H or a hydroxyl protecting group, R₄ and R₅ can combine to form a double bond, each P₃ can be independently H or a hydroxyl protecting group, and X₂, together with the carbon to which it is attached, can form a carbonyl or —(CH(OR₆))—, where R₆ can be H or a hydroxyl protecting group. In formula (VIA) or (VIB), R₃ can be a hydroxyl protecting group (e.g., a silyl), R₄ and R₅ can combine to form a double bond, each P₃ can be independently a hydroxyl protecting group, and X₂, together with the carbon to which it is attached, can form a carbonyl or —(CH(OR₆))—, where R₆ can be H or a hydroxyl protecting group (e.g., O can combine with R₆ to form an ester). In formula (VIB), P₄ can be a hydroxyl protecting group (e.g., O and P₄ can combine to form an ester).

Preparation of the compound of formula (VIB) from the compound of formula (VIA) can further involve

In a second aspect, the invention provides a method of preparing:

In some embodiments of the second aspect, the method involves:

-   -   (A) producing a compound of formula (IB) from a compound of         formula (IA), the compound of formula (IA) having the following         structure:

-   -   where     -   R₁ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₉)₂—, or NP₅, and         where each R₉ is independently H or —COOR₁₀, P₅ is an         N-protecting group, and R₁₀ is C₁₋₆ alkyl;     -   (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl         ether, and R₄ is H;     -   (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄         combine to form a double bond;     -   or     -   (a3) R₂ and R₃ combine to form a bond, and R₄ is H;     -   (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇         combine to form a double bond;     -   or     -   (b2) R₅ and R₆ combine to form a bond, and R₇ is H;     -   (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group;     -   or     -   (c2) R₈ and P₄ combine to form a double bond;     -   each P₃ is independently H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl;     -   the compound of formula (IB) having the following structure:

-   -   where each variable is as defined for formula (IA).

The method can involve (B) producing a compound of formula (IC) from the compound of formula (IB), the compound of formula (IC) having the following structure:

-   -   where each variable can be as defined for formula (IB).

The method can involve (C) producing a compound of formula (ID) from the compound of formula (IC), the compound of formula (ID) having the following structure:

-   -   where each P₃ is independently H or a hydroxyl protecting group,         and X₂ is oxo; or both P₃ groups and X₂, together with the atoms         to which each is attached, combine to form ketal; and each of         the remaining variables is as defined for formula (IC).

The method can further involve (D) producing eribulin or eribulin mesylate from the compound of formula (ID).

In formula (IA) or (IB), P₄ can be a hydroxyl protecting group (e.g., a silyl). In formula (IA) or (IB), R₂ and R₃ can combine to form a bond, and R₄ can be H. In formula (IA) or (IB), R₅ and R₆ can combine to form a bond, and R₇ can be H. In formula (IA) or (IB), R₈ can be H, and P₄ can be a hydroxyl protecting group (e.g., a silyl).

In formula (IA) or (IB), each P₃ can be independently a hydroxyl protecting group (e.g., a silyl). In formula (IC), P₃ can be H or a hydroxyl protecting group (e.g., a silyl).

In formula (IA), (IB), (IC), or (ID), P₁ can be a hydroxyl protecting group (e.g., a silyl). In formula (IA) or (IB), X can be O. In formula (IA), (IB), (IC), or (ID), P₂ is a hydroxyl protecting group (e.g., a silyl). In formula (IA), (IB), (IC), or (ID), X can be N, and P₁ and P₂, together with the atoms to which each is attached, can combine to form an aminal.

The method can further involve oxidizing the compound of formula (IB) (e.g., when R₈ is H) with an olefin metathesis catalyst, e.g., by reacting with an oxidizing agent capable of oxidizing an alcohol to a carbonyl group (e.g., Dess-Martin periodinane). If, P₄ is a hydroxyl protecting group (e.g., a silyl) in the compound of formula (IB), this compound can be reacted with a hydroxyl protecting group removing agent prior to oxidizing the compound of formula (IB).

Producing the compound of formula (IB) from the compound of formula (IA) can involve reacting the compound of formula (IA) with an olefin metathesis catalyst.

Producing the compound of formula (IC) can include oxidizing the compound of formula (IB), where, in the compound of formula (IB), R₈ is H, and P₄ is H, e.g., by reacting the compound of formula (IB) with an oxidizing agent capable of oxidizing an alcohol to a carbonyl group (e.g., Dess-Martin periodinane).

Producing the compound of formula (ID) can include reacting the compound of formula (IC) with a 1,4-reducing agent. The compound of formula (ID), in which each P₃ is independently a hydroxyl protecting group, can be reacted with a hydroxyl protecting group removing agent to afford tej compound of formula (ID), in which each P₃ is H or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal.

In formula (ID), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal. In formula (ID), P₁ can be H. In formula (ID), X can be O, and P₂ can be H. Producing eribulin or eribulin mesylate from the compound of formula (ID) can include aminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producing eribulin or eribulin mesylate from the compound of formula (ID) can involve reacting the compound of formula (ID) with an amino unmasking agent.

Eribulin mesylate can be produced by salifying eribulin with methanesulfonic acid.

In certain embodiments of the second aspect, the method involves:

-   -   (A) producing a compound of formula (IIB) from a compound of         formula (IIA) or a salt thereof:

-   -   where     -   each R is independently optionally substituted alkyl or         optionally substituted aryl;     -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃         combine to form a double bond;     -   or     -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   P₄ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl; and     -   the compound of formula (IIB) having the following structure:

-   -   (B) producing a compound of formula (ID) from the compound of         formula (IIB), the compound of formula (ID) having the following         structure:

-   -   and     -   (C) producing eribulin or eribulin mesylate from the compound of         formula (ID).

In formula (IIA), each R can be optionally substituted alkyl. In formula (IIA) or (IIB), P₁ can be a hydroxyl protecting group (e.g., a silyl). In formula (IIA) or (IIB), P₂ can be a hydroxyl protecting group (e.g., a silyl). In formula (IIA) or (IIB), R₁ and R₂ can form a bond, and R₃ can be H. In formula (IIA) or (IIB), P₄ can be a hydroxyl protecting group (e.g., a silyl). In formula (IIA), (IIB), or (ID), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal.

Producing the compound of formula (IIB) can involve reacting the compound of formula (IIA) with an organic base (e.g., an organic base having a pKa of 11±2 (e.g., DBU or trialkylamine (e.g., triethylamine))) and a Lewis acid (e.g., a salt of Li, Mg, or Zn (e.g., lithium chloride or zinc trifluoromethanesulfonate)).

Producing the compound of formula (ID) can involve reacting the compound of formula (IIB) with a hydroxyl protecting group removing agent.

In formula (ID), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal. In formula (ID), P₁ can be H. In formula (ID), X can be O, and P₂ can be H. Producing eribulin or eribulin mesylate from the compound of formula (ID) can include aminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producing eribulin or eribulin mesylate from the compound of formula (ID) can involve reacting the compound of formula (ID) with an amino unmasking agent.

Eribulin mesylate can be produced by salifying eribulin with methanesulfonic acid.

In certain embodiments of the second aspect, the method involves:

-   -   (A) producing a compound of formula (IIIB) from the compound of         formula (IIIA), the compound of formula (IIIA) having the         following structure:

-   -   where     -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃         combine to form a double bond;         -   or     -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;     -   X₃ is oxo, or X₃ combines with the carbon atom to which it is         attached to form a ketal, a thioketal, or —(CH(OP₅))—, where P₅         is H or a hydroxyl protecting group; each P₃ is independently H         or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups         and X₂, together with the atoms to which each is attached,         combine to form ketal;     -   P₄ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl;     -   the compound of formula (IIIB) having the following structure:

-   -   (B) producing a compound of formula (ID) from the compound of         formula (IIIB), the compound of formula (ID) having the         following structure:

-   -   and     -   (C) producing eribulin or eribulin mesylate from the compound of         formula (ID).

In formula (IIIA) or (IIIB), P₄ can be a hydroxyl protecting group (e.g., a silyl). In formula (IIIA) or (IIIB), R₁ and R₂ can form a bond, and R₃ can be H. In formula (IIIA) or (IIIB), X₃ can combine with the carbon atom to which it is attached to form —(CH(OP₅))—. In particular, in formula (IIIA) or (IIIB), P₅ can be H. In formula (IIIA) or (IIIB), P₁ can be a hydroxyl protecting group (e.g., silyl). In formula (IIIA) or (IIIB), P₂ can be a hydroxyl protecting group. In formula (IIIA), (IIIB), or (ID), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal.

Producing the compound of formula (IIIB) can involve reacting the compound of formula (IIIA) with an olefin metathesis catalyst.

Producing the compound of formula (ID) can involve oxidizing (e.g., by reacting with an oxidizing agent capable of oxidizing an alcohol to a carbonyl group) the compound of formula (IIIB), where, in the compound of formula (IIIB), X₃, together with the carbon to which it is attached, forms —(CH(OP₅))—, where P₅ is H.

Producing the compound of formula (ID) can also involve reacting the compound of formula (IIIB), where, in the compound of formula (IIIB), P₄ is a hydroxyl protecting group, and R₄ and R₅ combine to form a double bond, with a hydroxyl protecting group removing agent.

In formula (ID), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal. In formula (ID), P₁ can be H. In formula (ID), X can be O, and P₂ can be H. Producing eribulin or eribulin mesylate from the compound of formula (ID) can include aminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producing eribulin or eribulin mesylate from the compound of formula (ID) can involve reacting the compound of formula (ID) with an amino unmasking agent.

Eribulin mesylate can be produced by salifying eribulin with methanesulfonic acid.

In certain embodiments of the second aspect, the method includes:

-   -   (A) producing a compound of formula (IVB) from a compound of         formula (IVA), the compound of formula (IVA) having the         following structure:

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   a designates R stereogenic center, and Z is a sulfonate,         chloride, bromide, or iodide; or a designates S stereogenic         center, and Z is OR₁, where R₁ is a hydroxyl protecting group;     -   (i) R₂ is H or a hydroxyl protecting group, and R₃ and R₄         combine to form a double bond;     -   or     -   (ii) R₂ and R₃ combine to form a bond, and R₄ is H;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or         -   P₁ and P₂, together with the atoms to which each is             attached, combine to form an aminal or             1,3-oxazolidin-2-one-5-yl;     -   the compound of formula (IVB) having the following structure:

-   -   where         -   a designates R stereogenic center, b designates S             stereogenic center, and Z is a sulfonate, chloride, bromide,             or iodide;         -   or         -   a designates S stereogenic center, b designates R             stereogenic center, and Z is OR₁,         -   where R₁ is a hydroxyl protecting group;     -   (B) producing a compound of formula (ID) from the compound of         formula (IVB), the compound of formula (ID) having the following         structure:

-   -   and     -   (C) producing eribulin or eribulin mesylate from the compound of         formula (ID).

In formula (IVA) or (IVB), Y can be bromide. In formula (IVA) or (IVB), R₂ and R₃ can combine to form a bond, and R₄ can be H. In formula (IVA) or (IVB), P₁ can be a hydroxyl protecting group (e.g., a silyl). In formula (IVA) or (IVB), P₂ can be a hydroxyl protecting group (e.g., a silyl). In formula (IVA) or (IVB), Z can be a sulfonate. In formula (IVA) or (IVB), Z can be OR₁, where R₁ can be a hydroxyl protecting group (e.g., Z can be an ester, carbonate, or carbamate (e.g., Z can be an ester)). In formula (IVA), (IVB), or (ID), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal.

Producing the compound of formula (IVB) can involve reacting the compound of formula (IVA) with a Cr(II) salt and a Ni(II) salt. Producing the compound of formula (IVB) can involve subjecting the compound of formula (IVA) to Nozaki-Hiyama-Kishi reaction conditions.

Producing the compound of formula (ID) can involve the step of nucleophilic ring-closing of the compound of formula (IVB).

In formula (ID), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal. In formula (ID), P₁ can be H. In formula (ID), X can be O, and P₂ can be H. Producing eribulin or eribulin mesylate from the compound of formula (ID) can include aminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producing eribulin or eribulin mesylate from the compound of formula (ID) can involve reacting the compound of formula (ID) with an amino unmasking agent.

Eribulin mesylate can be produced by salifying eribulin with methanesulfonic acid.

In particular embodiments of the second aspect, the method includes:

-   -   (A) producing a compound of formula (VB) from a compound of         formula (VA):

-   -   where     -   Y is SO₂R₁, or COOR₁, where, when Y is SO₂R₁, R₁ is optionally         substituted aryl or optionally substituted non-enolizable alkyl,         and when Y is COOR₁, R₁ is optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo, or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   R₂ is optionally substituted alkyl, optionally substituted         arylalkyl, or optionally substituted aryl; and     -   X is O, and         -   each of P₁ and P₂ is independently a hydroxyl protecting             group,         -   or         -   P₁ and P₂, together with the atoms to which is each is             attached, combine to form a cyclic protected diol;     -   or     -   X is N, and         -   P₁ is H or a hydroxyl protecting group, and X and P₂ combine             to form optionally masked amino;         -   or         -   P₁ and P₂, together with the atoms to which each is             attached, combine to form an aminal or             1,3-oxazolidin-2-one-5-yl;     -   the compound of formula (VB) having the following structure:

-   -   where     -   (i) R₃ is H, R₄ is ether, and R₅ is H;     -   (ii) R₅ is H, and R₃ and R₄, together with the bond connecting         the atoms to which each is attached, combine to form a double         bond;     -   or     -   (iii) R₃ is H, and R₄ and R₅ combine to form a bond;     -   (B) producing a compound of formula (ID) from the compound of         formula (VB), the compound of formula (ID) having the following         structure:

-   -   and     -   (C) producing eribulin or eribulin mesylate from the compound of         formula (ID).

In formula (VA) or (VB), Y can be SO₂R₁ (e.g., R₁ can be optionally substituted aryl). In formula (VA) or (VB), R₂ can be optionally substituted alkyl (e.g., unsubstituted C₁₋₆ alkyl). In formula (VB), R₃ can be H, and R₄ and R₅ can combine to form a bond. In formula (VA), (VB), or (ID), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal.

Producing the compound of formula (VB) can involve reacting the compound of formula (VA) with a strong base (e.g., a tertiary C₄₋₆ alkoxide).

Producing the compound of formula (ID) can involve reacting the compound of formula (VB), in which Y is SO₂R₁, and R₁ is optionally substituted aryl, with an electron-transferring reducing agent (e.g., SmI₂, Mg(0), or Cr(III) with Mn(0)).

In formula (ID), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal. In formula (ID), P₁ can be H. In formula (ID), X can be O, and P₂ can be H. Producing eribulin or eribulin mesylate from the compound of formula (ID) can include aminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producing eribulin or eribulin mesylate from the compound of formula (ID) can involve reacting the compound of formula (ID) with an amino unmasking agent.

Eribulin mesylate can be produced by salifying eribulin with methanesulfonic acid.

In other embodiments of the second aspect, the method includes:

-   -   (A) producing a compound of formula (VIB) from a compound of         formula (VIA), the compound of formula (VIA) having the         following structure:

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine         to form a double bond, each P₃ is independently H or a hydroxyl         protecting group, and X₂, together with the carbon to which it         is attached, forms a carbonyl or —(CH(OR₆))—, where R₆ is H or a         hydroxyl protecting group;     -   or     -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and         -   each P₃ is independently H or a hydroxyl protecting group,             and X₂, together with the carbon to which it is attached,             forms a carbonyl or —(CH(OR₆))—;         -   or         -   both P₃ groups and X₂, together with the atoms to which each             is attached, combine to form ketal;     -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to         form a bond;     -   or     -   (b2) Z and R₂ combine to form a double bond, and R₁ is a         hydroxyl protecting group;     -   and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl; and     -   the compound of formula (VIB) having the following structure:

-   -   where P₄ is H or a hydroxyl protecting group;     -   (B) producing a compound of formula (VIC) from the compound of         formula (VIB), the compound of formula (VIC) having the         following structure:

-   -   (C) producing a compound of formula (ID) from the compound of         formula (VIC), the compound of formula (ID) having the following         structure:

-   -   and     -   (D) producing eribulin or eribulin mesylate from the compound of         formula (ID).

Producing the compound of formula (VIB) can include reacting the compound of formula (VIA) with a Cr(II) salt and a Ni(II) salt.

Producing the compound of formula (ID) can include reacting the compound of formula (VIB) with a hydroxyl protecting group removing agent.

In formula (ID), both P₃ groups and X₂, together with the atoms to which each is attached, can combine to form ketal. In formula (ID), P₁ can be H. In formula (ID), X can be O, and P₂ can be H. Producing eribulin or eribulin mesylate from the compound of formula (ID) can include aminating the compound of formula (ID).

In formula (ID), X and P₂ can combine to form a masked amino. Producing eribulin or eribulin mesylate from the compound of formula (ID) can involve reacting the compound of formula (ID) with an amino unmasking agent.

Eribulin mesylate can be produced by salifying eribulin with methanesulfonic acid.

In a third aspect, the invention provides a method of preparing an intermediate in the synthesis of eribulin, the method including performing a Prins reaction by contacting a compound of formula (VIIA) with a compound of formula (VIIB) and R₃OH,

-   -   where R₃ can be an optionally substituted acyl;     -   where the compound of formula (VIIA) can have the following         structure:

-   -   where     -   Y₁ is SO₂R₁ or COOR₁, and R₁ is optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;     -   X₁ is O, or X₁, together with the carbon to which it is         attached, forms a cyclic acetal; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl;     -   where the compound of formula (VIIB) can have the following         structure:

-   -   -   where P₃ is H or a hydroxyl protecting group; each P₄ is             independently a hydroxyl protecting group, or both P₄             groups, together with the atoms to which each is attached,             combine to form a cyclic protected diol; and R₄ is H or             —CH₂X₂CH₂CH═CH₂, where X₂ is O, —CH₂—, or NP₅, where P₅ is             sulfonyl;

    -   and where the intermediate is a compound of formula (VIIC):

Performing a Prins reaction can involve reacting the compound of formula (VIIA) with a Lewis acid (e.g., boron trifluoride or a solvate thereof).

In a fourth aspect, the invention provides a method of preparing an intermediate in the synthesis of eribulin, the method can involve:

-   -   (A) cleaving the double bond in a compound of formula (VIIIA) to         afford a compound of formula (VIIIB), the compound of formula         (VIIIA) having the structure:

-   -   where         -   X₁ can be oxo, or X₁, together with the carbon atom to which             it can be attached, forms a ketal or         -   —(CH(OP₃))—, where P₃ can be H or a hydroxyl protecting             group;         -   R₁ can be H or —CH₂OP₄;         -   each of P₁, P₂, and P₄ can be independently a hydroxyl             protecting group, or         -   P₁ and P₄, together with the atoms to which each can be             attached, can combine to form a cyclic protected diol; and     -   the compound of formula (VIIIB) having the structure:

-   -   (B) reacting the compound of formula (VIIIB) with a compound of         formula (VIIIB-a) to afford a compound of formula (VIIIC):

-   -   where R₂ can be H or —CH₂CH₂OP₅, and P₅ can be a hydroxyl         protecting group;     -   and the compound of formula (VIIIB-a) has the following         structure:

-   -   (C) reacting the compound of formula (VIIIC) with a dehydrating         agent to afford a compound of formula (VIIID):

-   -   (D) reacting the compound of formula (VIIID) with a         dihydroxylating agent to afford a compound of formula (VIIIE):

-   -   (E) preparing a compound of formula (VIIIF) through a reaction         sequence including reacting the compound of formula (VIIIE) with         N-bromosuccinimide to afford a first intermediate, reacting the         first intermediate with an acylating agent (e.g., a carboxylic         acid anhydride) to afford a second intermediate, and (a), when         R₂ can be —CH₂CH₂OP₅, contacting the second intermediate with a         reducing agent, or (b), when R₂ can be H, allylating the second         intermediate compound of formula (VIIIF):

-   -   where Z can be an ester or —OP₇, where P₇ can be H or a hydroxyl         protecting group, and R₃ can be —CH₂CH₂OP₅ or —CH₂CH═CH₂;     -   (F) reacting the compound of formula (VIIIF) with a 1,4-reducing         agent to afford a compound of formula (VIIIG):

and

-   -   (G) forming a compound of formula (VIIIH) through a reaction         sequence including reacting the compound of formula (VIIIG) with         a Brønsted acid and Y—H, where Y can be optionally substituted         C₁₋₆ alkyl, the compound of formula (VIIIH) having the following         structure:

-   -   where Y can be optionally substituted C₁₋₆ alkyl ether; R₂ can         be —CH₂CH₂OP₅; X₂ can be oxo, or X₂, together with the carbon to         which it can be attached, forms a ketal or —(CH(OP₆))—, where P₆         can be a hydroxyl protecting group.

In some embodiments of the fourth aspect, the method further includes:

-   -   (H) replacing P₂ in the compound of formula (VIIIH) with         —Si(R₄)₂H to afford a compound of formula (VIIIJ):

-   -   where each R₄ is independently optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;     -   (I) reacting the compound of formula (VIIIJ) with a Lewis acid         to afford a compound of formula (VIIIK):

-   -   where Y₁ is fluoro, chloro, or bromo; and     -   (J) reacting the compound of formula (VIIIK) with a hydroxyl         protecting group removing agent and then reacting with a         hydroxyl protecting agent to afford a compound of formula         (VIIIL):

-   -   where P₂ is a hydroxyl protecting group.

In a fifth aspect, the invention provides compounds of formulas (IA), (IB), (IC), (IIA), (IIB), (IIIA), (IIIB), (IVA), (IVB), (IVE), (VA), (VB), (VIA), (VIB), (VIIB), and (VIIC). The invention also provides compounds of formulas (VIIIC), (VIIID), (VIIIE), (VIIIF), (VIIIG), (VIIIH), (VIIIJ), (VIIIK), and (VIIIL).

A compound of the fifth aspect can be a compound of formula (IA) or (IB):

-   -   or a salt thereof,     -   where     -   R₁ is H or —CH₂X₁CH₂CH═CH₂, where X₁ is O, —C(R₉)₂—, or NP₅, and         where each R₉ is independently H or —COOR₁₀, P₅ is an         N-protecting group, and R₁₀ is C₁₋₆ alkyl;     -   (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl         ether, and R₄ is H;     -   (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄         combine to form a double bond;     -   or     -   (a3) R₂ and R₃ combine to form a bond, and R₄ is H;     -   (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇         combine to form a double bond;     -   or     -   (b2) R₅ and R₆ combine to form a bond, and R₇ is H;     -   (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group;     -   or     -   (c2) R₈ and P₄ combine to form a double bond;     -   each P₃ is independently H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

A compound of the fifth aspect can be a compound of formula (IC):

-   -   or a salt thereof,     -   where     -   each P₃ is independently a hydroxyl protecting group; and         -   X is O, P₁ is a hydroxyl protecting group, and P₂ is H or a             hydroxyl protecting group;         -   or         -   P₁ is a hydroxyl protecting group, and X and P₂ combine to             form optionally masked amino.

A compound of fifth aspect can be a compound of formula (IIA) or (IIB):

-   -   or a salt thereof,     -   where     -   each R is independently optionally substituted alkyl or         optionally substituted aryl;     -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃         combine to form a double bond;     -   or     -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   P₄ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

A compound of the fifth aspect can be a compound of formula (IIIA) or (IIIB):

-   -   or a salt thereof,     -   where     -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃         combine to form a double bond;     -   or     -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;     -   X₃ is oxo, or X₃ combines with the carbon atom to which it is         attached to form a ketal, a thioketal, or —(CH(OP₅))—, where P₅         is H or a hydroxyl protecting group;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   P₄ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

A compound of the fifth aspect can be a compound of formula (IVA) or (IVB):

-   -   or a salt thereof,     -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   (a1) a designates R stereogenic center, b designates S         stereogenic center, and Z is a sulfonate, chloride, bromide, or         iodide;         -   or     -   (a2) a designates S stereogenic center, b designates R         stereogenic center, and Z is OR₁,         -   where R₁ is a hydroxyl protecting group;     -   (b1) R₂ is H or a hydroxyl protecting group, and R₃ and R₄         combine to form a double bond;         -   or     -   (b2) R₂ and R₃ combine to form a bond, and R₄ is H;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl

A compound of the fifth aspect can be a compound of formula (VA) or (VB):

-   -   or a salt thereof,     -   where     -   Y is SO₂R₁, or COOR₁, where, when Y is SO₂R₁, R₁ is optionally         substituted aryl or optionally substituted non-enolizable alkyl,         and when Y is COOR₁, R₁ is optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo, or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   R₂ is optionally substituted alkyl, optionally substituted         arylalkyl, or optionally substituted aryl; and     -   X is O, and         -   each of P₁ and P₂ is independently a hydroxyl protecting             group,         -   or         -   P₁ and P₂, together with the atoms to which is each is             attached, combine to form a cyclic protected diol;     -   or     -   X is N, and         -   P₁ is H or a hydroxyl protecting group, and X and P₂ combine             to form optionally masked amino;         -   or         -   P₁ and P₂, together with the atoms to which each is             attached, combine to form an aminal or             1,3-oxazolidin-2-one-5-yl.

A compound of formula (VIA) or (VIB):

-   -   or a salt thereof,     -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   P₄ is H or a hydroxyl protecting group;     -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine         to form a double bond, each P₃ is independently H or a hydroxyl         protecting group, and X₂, together with the carbon to which it         is attached, forms a carbonyl or —(CH(OR₆))—, where R₆ is H or a         hydroxyl protecting group;     -   or     -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and         -   each P₃ is independently H or a hydroxyl protecting group,             and X₂, together with the carbon to which it is attached,             forms a carbonyl or —(CH(OR₆))—;         -   or         -   both P₃ groups and X₂, together with the atoms to which each             is attached, combine to form ketal;     -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to         form a bond;     -   or     -   (b2) Z and R₂ combine to form a double bond, and R₁ is a         hydroxyl protecting group;     -   and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

A compound of the fifth aspect can be a compound of formula (VIIC):

-   -   or a salt thereof,     -   where     -   a designates R stereogenic center or S stereogenic center;     -   Y₁ is SO₂R₁ or COOR₁, and R₁ is optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;

-   -   -   where P₃ is H or a hydroxyl protecting group; each P₄ is             independently a hydroxyl protecting group, or both P₄             groups, together with the atoms to which each is attached,             combine to form a cyclic protected diol; and R₄ is H or             —CH₂X₂CH₂CH═CH₂, where X₂ is O, —CH₂—, or NP₅, where P₅ is             sulfonyl;

    -   R₃ is an optionally substituted acyl; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

A compound of the fifth aspect can be a compound of formula (VIIB):

-   -   where         -   P₃ is a hydroxyl protecting group; each P₄ is independently             a hydroxyl protecting group, or both P₄ groups, together             with the atoms to which each is attached, combine to form a             cyclic protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, where             X₂ is O, —CH₂—, or NP₅, where P₅ is sulfonyl.

A compound of the fifth aspect can be a compound of formula (IVE):

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   Z is an ester, a sulfonate, chloride, bromide, or iodide;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal; and     -   (a1) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine         to form a double bond;     -   or     -   (a2) R₂ and R₃ combine to form a bond, and R₄ is H;     -   (b1) R₇ and R₈ combine to form a bond, and R₉ is H;     -   or     -   (b2) R₇ is H or a hydroxyl protecting group, and R₈ and R₉         combine to form a double bond;     -   (c1) X₃ is oxo and R₁₀ is H or —OP₅, where P₅ is H or an ether         hydroxyl protecting group;     -   or         (c2) X₃ and R₁₀ together with the carbon atom to which they are         attached form —CH₂OP₆, wherein P₆ is H or a hydroxyl protecting         group, and R₁₀ is H.

DEFINITIONS

Compounds useful in the invention may be isotopically labeled compounds. Useful isotopes include hydrogen, carbon, nitrogen, and oxygen (e.g., ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, and ¹⁷O). Isotopically-labeled compounds can be prepared by synthesizing a compound using a readily available isotopically-labeled reagent in place of a non-isotopically-labeled reagent.

For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as hydrogen atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C₂ alkyl group has the formula —CH₂CH₃. When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.

By “acetal” is meant —O—(CHR)—O—, where R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

By “acyl” is meant —C(O)R, where R is H, alkyl, alkenyl, aryl, or arylalkyl. In exemplary acyl groups, R is H, C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, or C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, or C₃₋₆ alkenyl), C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, or C₈₋₁₅ aryl), monocyclic C₁₋₆ heteroaryl (e.g., monocyclic C₁₋₄ or C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g., C₄₋₁₀ heteroaryl), (C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₁₋₆)heteroaryl(C₁₋₆)alkyl, or (C₄₋₁₉)heteroaryl(C₁₋₆)alkyl. As defined herein, any heteroaryl group present in an acyl group has from 1 to 4 heteroatoms selected independently from O, N, and S. An acyl group can be unsubstituted or substituted (e.g., optionally substituted acyl). In the optionally substituted acyl group, the substituent R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

By “acylating agent” is meant a compound that reacts with an amine or a hydroxyl group to produce an amide or an ester, respectively. An acylating agent has a formula R-LG, where R is acyl, and LG is halogen, carbonate, or —OR′, where R′ is acyl.

By “alkoxide” is meant an anionic compound RO⁻, where R is alkyl. A counterion for alkoxide can be an alkali metal cation, an alkali earth metal cation, or a tetraalkylammonium cation. Alkoxide can be optionally substituted in the same manner as alkyl.

By “alkoxy” is meant —OR, where R is alkyl. Alkoxy can be optionally substituted in the same manner as alkyl.

By “alkoxyalkyl” is meant —OR, where R is alkyl substituted by alkoxy. Each portion of the alkoxyalkyl can be optionally substituted in the same manner as alkyl.

By “alkyl” is meant a straight or branched chain saturated cyclic (i.e., cycloalkyl) or acyclic hydrocarbon group of from 1 to 12 carbons, unless otherwise specified. Exemplary alkyl groups include C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl. Specific examples include methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl, and the like. Alkyl group can be optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, alkoxy, aryloxy, arylalkyloxy, oxo, alkylthio, alkylenedithio, alkylamino, [alkenyl]alkylamino, [aryl]alkylamino, [arylalkyl]alkylamino, dialkylamino, silyl, sulfonyl, cyano, nitro, carboxyl, and azido.

By “alkylamino” is meant —NHR, where R is alkyl. By “[alkenyl]alkylamino” is meant —NRR′, where R is alkyl, and R′ is alkenyl. By “[aryl]alkylamino” is meant —NRR′, where R is alkyl, and R′ is aryl. By “[arylalkyl]alkylamino” is meant —NRR′, where R is alkyl, and R′ is arylalkyl. By “dialkylamino” is meant —NR₂, where each R is alkyl, selected independently.

By “alkylene” is meant a divalent alkyl group. Alkylene groups can be optionally substituted in the same manner as alkyl groups. For example, a C₁ alkylene group is —CH₂—.

By “alkylenedithio” is meant —S-alkylene-S—. Alkylenedithio can be optionally substituted in the same manner as an alkylene group.

By “alkylthio” is meant —SR, where R is alkyl. Alkylthio can be optionally substituted in the same manner as an alkyl group.

By “alkenyl” is meant a straight or branched chain cyclic or acyclic hydrocarbon group of, unless otherwise specified, from 2 to 12 carbons and containing one or more carbon-carbon double bonds. Exemplary alkenyl groups include C₂₋₆, C₂₋₇, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl. Specific examples include ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), and the like. Alkenyl group can be optionally substituted in the same manner as alkyl groups. Alkenyl groups, used in any context herein, may also be substituted with an aryl group.

By “amido” is meant —NHR, where R is acyl. Amido can be optionally substituted in the same manner as acyl.

By “aminal” is meant —O—CR₂—NR′—, where each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl, or both R groups are together optionally substituted alkylene, and R′ is H or an N-protecting group. In particular, R′ can be an N-protecting group (e.g., Boc).

By “amino” is meant —NR₂, where N and R₂ combine to form azido, or each R is independently H or an N-protecting group, or both R combine to form an N-protecting group. Amino can be unmasked, when each R is H, or masked, when at least one R is not H. Thus, optionally masked amino can be masked or unmasked amino.

By “aryl” is meant a monocyclic or multicyclic ring system having one or more aromatic rings, where the ring system is carbocyclic or heterocyclic. Heterocyclic aryl groups are also referred to as heteroaryl groups. A heteroaryl group includes 1 to 4 atoms selected independently from O, N, and S. Exemplary carbocyclic aryl groups include C₆₋₂₀, C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl. A preferred aryl group is a C6-10 aryl group. Specific examples of carbocyclic aryl groups include phenyl, indanyl, indenyl, naphthyl, phenanthryl, anthracyl, and fluorenyl. Exemplary heteroaryl groups include monocylic rings having from 1 to 4 heteroatoms selected independently from O, N, and S and from 1 to 6 carbons (e.g., C₁₋₆, C₁₋₄, and C₂₋₆). Monocyclic heteroaryl groups preferably include from 5 to 9 ring members. Other heteroaryl groups preferably include from 4 to 19 carbon atoms (e.g., C₄₋₁₀). Specific examples of heteroaryl groups include pyridinyl, quinolinyl, dihydroquinolinyl, isoquinolinyl, quinazolinyl, dihydroquinazolyl, and tetrahydroquinazolyl. Aryl group can be optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, aryl, arylalkyl, halogen, alkoxy, aryloxy, arylalkyloxy, alkylthio, alkylenedithio, alkylamino, [alkenyl]alkylamino, [aryl]alkylamino, [arylalkyl]alkylamino, dialkylamino, silyl, sulfonyl, cyano, nitro, carboxyl, and azido.

By “arylalkyl” is meant —R′R″, where R′ is alkylene, and R″ is aryl. Arylalkyl can be optionally substituted in the same manner as defined for each R′ and R″ group.

By “arylalkyloxy” is meant —OR, where R is arylalkyl. Arylalkyloxy can be optionally substituted in the same manner as defined for arylalkyl.

By “aryloxy” is meant —OR, where R is aryl. Aryloxy can be optionally substituted in the same manner as aryl.

By “azido” is meant —N₃.

By “boronate” is meant —OBRO—, where R is alkyl, alkenyl, aryl, arylalkyl, alkoxy, or 2,6-diacetamidophenyl. Boronate can be substituted, when R is a substituted alkyl, substituted alkenyl, substituted aryl, substituted arylalkyl, or substituted alkoxy. Alternatively, boronate can be unsubstituted, when R is unsubstituted alkyl, unsubstituted alkenyl, aryl, unsubstituted arylalkyl, unsubstituted alkoxy, or 2,6-diacetamidophenyl.

By “carbamate” is meant a group, when a hydroxyl protecting group, having the formula —OC(O)NR₂, or, when an amine protecting group, having the formula —NR′—C(O)OR, where each R and R′ is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

By “carbonate” is meant —OC(O)OR, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

By “carbonyl” is meant —C(O)—.

By “carboxyl” is meant —C(O)OH, in free acid, ionized, or salt form.

By “carboxylic acid” is meant R—OH, where R is optionally substituted acyl.

By “carboxylic acid anhydride” is meant R—O—R, where each R is independently optionally substituted acyl.

By “dicarbonyl” is meant —C(O)—C(O)—.

By “ester” is meant —OC(O)R, where —C(O)R is an optionally substituted acyl group.

By “ether” is meant —OR, where R is alkyl, alkenyl, arylalkyl, silyl, or 2-tetrahydropyranyl. Ether can be optionally substituted as defined for each R group.

By “halogen” is meant fluoro, chloro, bromo, or iodo.

By “hydroxyl protecting group” is meant any group capable of protecting the oxygen atom to which it is attached from reacting or bonding. Hydroxyl protecting groups are known in the art, e.g., as described in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006. Exemplary protecting groups (with the oxygen atom to which they are attached) are independently selected from the group consisting of esters, carbonates, carbamates, sulfonates, and ethers. In exemplary ester hydroxyl protecting groups, R of the acyl group is C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl), carbocyclic C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl), monocyclic C₁₋₆ heteroaryl (e.g., C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g., C₄₋₁₀ heteroaryl), (C₆₋₁₆)aryl(C₁₋₆)alkyl, (C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, or (C₁₋₆)heteroaryl(C₁₋₆)alkyl. Specific examples of acyl groups for use in esters include formyl, benzoylformyl, acetyl (e.g., unsubstituted or chloroacetyl, trifluoroacetyl, methoxyacetyl, triphenylmethoxyacetyl, and p-chlorophenoxyacetyl), 3-phenylpropionyl, 4-oxopentanoyl, 4,4-(ethylenedithio)pentanoyl, pivaloyl (Piv), vinylpivaloyl, crotonoyl, 4-methoxy-crotonoyl, naphthoyl (e.g., 1- or 2-naphthoyl), and benzoyl (e.g., unsubstituted or substituted, e.g., p-methoxybenzoyl, phthaloyl (including salts, such a triethylamine and potassium), p-bromobenzoyl, and 2,4,6-trimethylbenzoyl). As defined herein, any heteroaryl group present in an ester group has from 1 to 4 heteroatoms selected independently from O, N, and S. In exemplary carbonate hydroxyl protecting groups, R is C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂₃ and C₃₋₆ alkenyl), carbocyclic C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl), monocyclic C₁₋₆ heteroaryl (e.g., C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g., C₄₋₁₀ heteroaryl), (C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, or (C₁₋₆)heteroaryl(C₁₋₆)alkyl. Specific examples include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, t-butyl, p-nitrobenzyl, and benzyl carbonates. As defined herein, any heteroaryl group present in a carbonate group has from 1 to 4 heteroatoms selected independently from O, N, and S. In exemplary carbamate hydroxyl protecting groups, each R is independently H, C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl), carbocyclic C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, and C₈₋₁₅ aryl), monocyclic C₁₋₆ heteroaryl (e.g., C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g., C₄₋₁₀ heteroaryl), (C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, or (C₁₋₆)heteroaryl(C₁₋₆)alkyl. Specific examples include N-phenyl and N-methyl-N-(o-nitrophenyl) carbamates. As defined herein, any heteroaryl group present in a carbamate group has from 1 to 4 heteroatoms selected independently from O, N, and S. Exemplary ether hydroxyl protecting groups include C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, and C₃₋₆ alkenyl), (C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₄₋₁₀)heteroaryl(C₁₋₆)alkyl, (C₁₋₆)heteroaryl(C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl, (C₁₋₆)alkylthio(C₁₋₆)alkyl, (C₆₋₁₀)aryl(C₁₋₆)alkoxy(C₁₋₆)alkyl, and silyl (e.g., tri(C₁₋₆ alkyl)silyl, tri(C₆₋₁₀ aryl or C₁₋₆ heteroaryl)silyl, di(C₆₋₁₀ aryl or C₁₋₆ heteroaryl)(C₁₋₆ alkyl)silyl, and (C₆₋₁₀ aryl or C₁₋₆ heteroaryl)di(C₁₋₆ alkyl)silyl). Specific examples of alkylethers include methyl and t-butyl, and an example of an alkenyl ether is allyl. Ether hydroxyl protecting groups can be used to protect a carboxyl group (e.g., with a C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, and C₃₋₆ alkyl), (C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₁₋₆)alkoxy(C₁₋₆)alkyl, (C₁₋₆)alkylthio(C₁₋₆)alkyl, or (C₆₋₁₀)aryl(C₁₋₆)alkoxy(C₁₋₆)alkyl). Examples of alkoxyalkyls and alkylthioalkyls that can be used as ether hydroxyl protecting groups include methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, and β-(trimethylsilyl)ethoxymethyl. Examples of arylalkyl groups that can be used as ether hydroxyl protecting groups include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, triphenylmethyl (trityl), o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, naphthylmethyl, and 2- and 4-picolyl ethers. Specific examples of silylethers include trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBS), t-butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), and triphenylsilyl (TPS) ethers. An example of an arylalkyloxyalkylether is benzyloxymethyl ether. As defined herein, any heteroaryl group present in an ether group has from 1 to 4 heteroatoms selected independently from O, N, and S. Vicinal or 1,3-diols may be protected with a diol protecting group (e.g., to produce a “cyclic protected diol”), such as acetal (e.g., containing C₁₋₆ alkylene), ketal (e.g., containing C₃₋₆ alkylene or C₃₋₆ cycloalkyl), cyclic silylene, cyclic carbonate, and cyclic boronate. Examples of acetal and ketal groups include methylene-dioxo, ethylidene-dioxo, benzylidene-dioxo, isopropylidene-dioxo, cyclohexylidene-dioxo, and cyclopentylidene-dioxo. An example of a cyclic silylene is di-t-butylsilylene. Another diol protecting group is 1,1,3,3-tetraisopropylsiloxanediyl. Examples of cyclic boronates include methyl, ethyl, phenyl, and 2,6-diacetamidophenyl boronates. Protecting groups may be substituted as is known in the art; for example, aryl and arylalkyl groups, such as phenyl, benzyl, naphthyl, or pyridinyl, can be substituted with C₁₋₆ alkyl, C₁₋₆ alkoxy, nitro, cyano, carboxyl, or halogen. Alkyl groups, such as methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, and sec-butyl, and alkenyl groups, such as vinyl and allyl, can also be substituted with oxo, arylsulfonyl, halogen, and trialkylsilyl groups. Preferred protecting groups are TBS and Piv. Protecting groups that are orthogonal are removed under different conditions, as in known in the art.

By “imido” is meant —NR₂, where each R is independently optionally substituted acyl.

By “ketal” is meant —O—CR₂—O—, where each R is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl, or both R groups are together optionally substituted alkylene.

By “macrocyclization” is meant a reaction converting a non-macrocyclic compound into a compound containing at least one n-membered ring, where n is equal to or greater than 16.

By “non-enolizable” is meant a group that, either alone or in combination with a group to which it is attached, cannot form an enol through a deprotonation/reprotonation sequence. For example, a “non-enolizable alkyl” can be bonded to a sulfone group or to a carbonyl group through a quaternary carbon atom (i.e., the carbon atom that is not bonded to a hydrogen atom).

By “non-macrocyclic” is meant a compound not containing rings or containing one or more m-membered rings, where m is less than or equal to 15.

By “N-protecting group” is meant a group protecting a nitrogen atom in a molecule from participating in one or more undesirable reactions during chemical synthesis (e.g., oxidation reactions, or certain nucleophilic and electrophilic substitutions). Commonly used N-protecting groups are disclosed in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006. Exemplary N-protecting groups include acyl (e.g., formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, and 4-bromobenzoyl); sulfonyl-containing groups (e.g., benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl); carbamate forming groups (e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyl oxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl), arylalkyl (e.g., triphenylmethyl); silyl groups (e.g., trimethylsilyl); and imine-forming groups (e.g., diphenylmethylene). Preferred N-protecting groups are acetyl, benzoyl, phenylsulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

By “1,3-oxazolidin-2-one-5-yl” is meant 1,3-oxazolidin-2-one-5-yl, in which the nitrogen atom is substituted with H or an N-protecting group (e.g., Boc).

By “oxo” or (O) is meant ═O.

By “pharmaceutically acceptable salt” is meant a salt within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P. H. Stahl and C. G. Wermuth), Wiley-VCH, 2008. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts and the like. A preferred salt is the mesylate salt.

By “silyl” is meant —SiR₃, where each R is independently alkyl, alkenyl, aryl, or arylalkyl. Examples of silyl groups include tri(C₁₋₆ alkyl)silyl, tri(C₆₋₁₀ aryl or C₁₋₆ heteroaryl)silyl, di(C₆₋₁₀ aryl or C₁₋₆ heteroaryl)(C₁₋₆ alkyl)silyl, and (C₆₋₁₀ aryl or C₁₋₆ heteroaryl)di(C₁₋₆ alkyl)silyl. It will be understood that, when a silyl group includes two or more alkyl, alkenyl, aryl, heteroaryl, or arylalkyl groups, these groups are independently selected. As defined herein, any heteroaryl group present in a silyl group has from 1 to 4 heteroatoms selected independently from O, N, and S. Silyl can be optionally substituted in the same manner as defined for each R group.

By “silylene” is meant —SiR₂—, where each R is independently alkyl, alkenyl, aryl, arylalkyl, or alkoxy. By “dialkylsilylene” is meant a silylene, where each R is alkyl. Silylene can be optionally substituted in the same manner as defined for each R group.

By “strong base” is meant a Brønsted base, the conjugate acid of which has pKa that is greater than or equal to 13. Non-limiting examples of strong bases include alkyl alkali metals (e.g., butyl lithium or Schlosser's base), Grignard reagents (e.g., alkyl magnesium halide), alkoxides (e.g., tertiary alkoxides, such as t-butoxide), amides (e.g., diisopropylamide, tetramethylpiperidide, or bis(trimethylsilyl)amide), and phosphazene bases (e.g., Schwesinger base).

By “sulfonamide” is meant —NR, where R is sulfonyl.

By “sulfonate” is meant —OS(O)₂R, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl. In exemplary sulfonates, R is C₁₋₁₂ alkyl (e.g., C₁₋₈, C₁₋₆, C₁₋₄, C₂₋₇, C₃₋₁₂, or C₃₋₆ alkyl), C₂₋₁₂ alkenyl (e.g., C₂₋₈, C₂₋₆, C₂₋₄, C₃₋₁₂, or C₃₋₆ alkenyl), carbocyclic C₆₋₂₀ aryl (e.g., C₆₋₁₅, C₆₋₁₀, C₈₋₂₀, or C₈₋₁₅ aryl), monocyclic C₁₋₆ heteroaryl (e.g., C₁₋₄ and C₂₋₆ heteroaryl), C₄₋₁₉ heteroaryl (e.g., C₄₋₁₀ heteroaryl), (C₆₋₁₅)aryl(C₁₋₆)alkyl, (C₄₋₁₉)heteroaryl(C₁₋₆)alkyl, or (C₁₋₆)heteroaryl(C₁₋₆)alkyl. As defined herein, any heteroaryl group present in a sulfonate group has from 1 to 4 heteroatoms selected independently from O, N, and S.

By “sulfonyl” is meant —S(O)₂R, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, or silyl. Preferred R groups for sulfonyl are the same as those described above for sulfonates.

By “thioacetal” is meant —S—(CHR)—S—, where R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

By “thioketal” is meant —S—(CR₂)—S—, where each R is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

By “triflate” is meant trifluoromethanesulfonate.

The pKa values recited herein refer to the pKa values of a conjugate Brønsted acid in water at room temperature, unless stated otherwise.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a scheme showing preparation of eribulin through a C.15-C.16 bond-forming macrocyclization.

FIG. 2 is a scheme showing preparation of eribulin through a C.2-C.3 bond-forming macrocyclization.

FIG. 3 is a scheme showing preparation of eribulin through a C.3-C.4 bond-forming macrocyclization.

FIG. 4 is a scheme showing preparation of eribulin through a C.19-C.20 bond-forming macrocyclization.

FIG. 5 is a scheme showing preparation of eribulin through a C.0-C.1 bond-forming macrocyclization.

FIG. 6 is a scheme showing preparation of eribulin through a C.26-C.27 bond-forming macrocyclization.

FIG. 7 is a depiction of a co-crystal of 2-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3,9-dihydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate and its C3-epimer.

DETAILED DESCRIPTION

The present invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclizations. The macrocyclizations of the present invention involve subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., catalytic Ring-Closing Olefin Metathesis, an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), Nozaki-Hiyama-Kishi reaction, or Dieckmann reaction) to afford a macrocyclic intermediate (e.g., a compound of formula (IB), (IIB), (IIIB), (IVB), (VB), or (VIB)). The carbon-carbon bond forming reaction provides a C.0-C.1, C.2-C.3, C.3-C.4, C.15-C.16, C.19-C.20, or C.26-C.27 bond in the structure of eribulin or a pharmaceutically acceptable salt thereof. The carbon-atom numbering scheme for eribulin and pharmaceutically acceptable salts thereof is shown in Chart 1.

The invention also provides intermediates in the synthesis of eribulin and methods of preparing the same, as described herein.

C.15-C.16 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbon bond-forming reaction (e.g., catalytic Ring-Closing olefin Metathesis (RCM)) that provides a C.15-C.16 bond in eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate). The general synthetic sequence including RCM that can be used to prepare eribulin or a pharmaceutically acceptable salt thereof (e.g., a mesylate salt) is shown in FIG. 1. As shown in FIG. 1, the non-macrocyclic intermediate in the synthesis of eribulin can be a compound of formula (IA):

-   -   where     -   R₁ is H or —CH₂X₁CH₂CH═CH₂, wherein X₁ is O, —C(R₉)₂—, or NP₅,         and where each R₉ is independently H or —COOR₁₀, P₅ is an         N-protecting group, and R₁₀ is C₁₋₆ alkyl;     -   (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl         ether, and R₄ is H;     -   (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄         combine to form a double bond;     -   or     -   (a3) R₂ and R₃ combine to form a bond, and R₄ is H;     -   (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇         combine to form a double bond;     -   or     -   (b2) R₅ and R₆ combine to form a bond, and R₇ is H;     -   (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group;     -   or     -   (c2) R₈ and P₄ combine to form a double bond;     -   each P₃ is independently H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

An intermediate in the synthesis of eribulin can be a compound of formula (IB), which can be produced by reacting the compound of formula (IA) with an olefin metathesis catalyst (e.g., a ruthenium-carbene complex). The compound of formula (IB) has the following structure:

-   -   where all variables are as defined for compound of formula (IA).

The catalysts that can be used to convert the compound of formula (IA) to the compound of formula (IB) can be those known in the art. Olefin metathesis catalysts include Ru-carbene complexes (e.g., Grubbs and Hoveyda-Grubbs catalysts).

The compound of formula (IB) can be reacted with a hydroxyl protecting group removing agent and, optionally, an oxidizing agent (e.g., when R₈ is H in the compound of formula (IB)) capable of converting an alcohol to a carbonyl group (e.g., capable of converting an allylic alcohol to an enone) to afford the compound of formula (IC):

-   -   where P₁, P₂, P₃, and X are as defined for compound of formula         (IB).

The hydroxyl protecting group removing agent used in the step forming the compound of formula (IC) can be a Brønsted acid (e.g., a carboxylic acid, such as a carboxylic acid having a pKa of 4±1).

The compound of formula (ID) can be prepared from the compound of formula (IC) by a synthesis involving reacting the compound of formula (IC) with a 1,4-reducing agent to afford a compound of formula (ID):

-   -   where P₁, P₂, and X are as defined for compound of formula (IC);         and     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal.

The 1,4-reducing agents include copper (I) hydrides, which can be isolated (e.g., Stryker's reagent) or prepared in situ (e.g., from a copper (I) or copper (II) salt and a hydride source). Catalytic quantities of a copper salt (either copper (I) or copper (II) salt) in combination with stoichiometric or superstoichiometric quantities of a hydride source (e.g., a borohydride salt, borane, PMHS, or a hydrosilane (e.g., Ph₂SiH₂)). A non-limiting example of the reaction conditions that can be used for conversion of the compound of formula (IC) to the compound of formula (ID) are described, e.g., in Baker et al., Org. Lett., 10:289-292, 2008, the disclosure of which is incorporated herein by reference. Other metals can be used to catalyze 1,4-reduction of the compound of formula (IC) to afford the compound of formula (ID), e.g., Ru, Pd, and Ir compounds.

If P₁ is a hydroxyl protecting group in the compound of formula (ID), the compound of formula (ID) can be reacted with a hydroxyl protecting group removing agent to afford:

-   -   where     -   both P₃ groups and X₂, together with the atoms to which each is         attached, combine to form ketal; and         -   X is O, and each of P₁ and P₂ is H,         -   or         -   P₁ is H, and X and P₂ combine to form optionally masked             amino.

The compound of formula (ID) (e.g., the compound of formula (ID), in which X is O, P₂ is H, and both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal) can be aminated to afford eribulin, e.g., using sulfonylation followed by the treatment with a nitrogen source (e.g., ammonia (e.g., aqueous ammonia) or sulfamic acid). When the nitrogen source is not ammonia or sulfamic acid, further contacting with an amino unmasking agent may be used to afford eribulin. The compound of formula (ID), in which P₁ is a hydroxyl protecting group, can be reacted with a hydroxyl protecting group removing agent prior to the amination reaction. Alternatively, the compound of formula (ID) (in which P₁ is H, X and P₂ combine to form a masked amino, and both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal) can be reacted with an amino unmasking agent to afford eribulin, as described herein. Eribulin mesylate can then be produced by salification of eribulin with methanesulfonic acid. The details of the amination and salification reactions are described below.

The compound of formula (IA) can be prepared from a compound of formula (IE):

-   -   where     -   R₁ is H or —CH₂X₁CH₂CHCH₂, wherein X₁ is O, —O(R₉)₂—, or NP₅,         and where each R₉ is independently H or —COOR₁₀, P₅ is an         N-protecting group, and R₁₀ is C₁₋₆ alkyl;     -   (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl         ether, and R₄ is H;     -   (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄         combine to form a double bond;     -   or     -   (a3) R₂ and R₃ combine to form a bond, and R₄ is H;     -   (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇         combine to form a double bond;     -   or     -   (b2) R₅ and R₆ combine to form a bond, and R₇ is H;     -   (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group;     -   or     -   (c2) R₈ and P₄ combine to form a double bond;     -   each P₃ is independently H or a hydroxyl protecting group;     -   Y is SO₂R₁₁ and R₁₁ is optionally substituted aryl or optionally         substituted non-enolizable alkyl; or Y is COOR₁₁, and R₁₁ is         optionally substituted alkyl, optionally substituted aryl, or         optionally substituted arylalkyl;     -   X₃ is oxo, or X₃, together with the carbon atom to which it is         attached, forms —(CH(OH))—; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

In some embodiments, the preparation of the compound of formula (IA) from the compound of formula (IE) involves a decarboxylation reaction (when X₃ is oxo, and Y is COOR₁₁) or a desulfonylation (when X₃ is oxo, and Y is SO₂R₁₁) reaction. The conditions for the decarboxylation or desulfonylation reaction can be those described herein. The preparation of the compound of formula (IA) from the compound of formula (IE) can further involve oxidizing the compound of formula (IE) (e.g., the compound of formula (IE), in which X₃, together with the carbon atom to which it is attached, forms —(CH(OH))—), e.g., by contacting with an oxidizing agent capable of oxidizing an alcohol to a carbonyl group.

C.2-C.3 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbon bond-forming reaction (e.g., Horner-Wadsworth-Emmons reaction) that provides a C.2-C.3 bond in eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate). The general synthetic sequence including the Horner-Wadsworth-Emmons reaction that can be used to prepare eribulin or a pharmaceutically acceptable salt thereof (e.g., a mesylate salt) is shown in FIG. 2. As shown in FIG. 2, the non-macrocyclic intermediate can be a compound of formula (IIA):

-   -   where     -   each R is independently optionally substituted alkyl or         optionally substituted aryl;     -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃         combine to form a double bond;     -   or     -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   P₄ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

The intermediate in the synthesis of eribulin can be a compound of formula (IIB), which can be produced from the compound of formula (IIA) using Horner-Wadsworth-Emmons reaction. The compound of formula (IIB) has the following structure:

-   -   where all variables are as defined for the compound of formula         (IIA).

The reaction conditions that can be used to convert the compound of formula (IIA) into the compound of formula (IIB) include those known in the art for Horner-Wadsworth-Emmons reaction, e.g., Masamune-Roush conditions or Helquist protocol. In particular, the compound of formula (IIA) can be reacted with an organic base (e.g., an organic base, the conjugate acid of which has a pKa of from 11±2) and a Lewis acid (e.g., a salt of Li, Mg, or Zn). Non-limiting examples of an organic base that can be used in the Horner-Wadsworth-Emmons reaction include trialkylamines (e.g., triethylamine or Hünig's base), DBU, and DBN. Non-limiting examples of Lewis acids that can be used in the Horner-Wadsworth-Emmons reaction include LiCI, Zn(OTf)₂, and MgCl₂.

The compound of formula (IIB) can be converted to a compound of formula (ID):

-   -   where     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

In a non-limiting example, the synthesis of the compound of formula (ID) from the compound of formula (IIB) can involve reacting the compound of formula (IIB) (e.g., the compound of formula (IIB), in which P₄ is a protecting group, R₁ and R₂ form a bond, and R₃ is H) with a hydroxyl protecting group removing agent.

The compound of formula (ID) (in which X is O, P₁ and P₂ are H, and both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal) can be aminated to afford eribulin, as described herein. Alternatively, the compound of formula (ID) (in which P₁ is H, X and P₂ combine to form a masked amino, and both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal) can be reacted with an amino unmasking agent to afford eribulin, as described herein. Eribulin mesylate can be produced by salification of eribulin, as described herein.

The compound of formula (IIA) can be prepared from a compound of formula (IIC):

-   -   where     -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃         combine to form a double bond;     -   or     -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;     -   R₄ is OH, and R₅ is H, or R₄ and R₅ combine to form a double         bond;     -   R₆ is —OP₅ or CH₂P(O)(OR₆)₂, where P₅ is an ether hydroxyl         protecting group, and each R₆ is independently optionally         substituted alkyl or optionally substituted aryl;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   P₄ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

In some embodiments, the preparation of the compound of formula (IIA) from the compound of formula (IIC) can involve performing hydroboration/oxidation reaction on the compound of formula (IIC) (e.g., the compound of formula (IIC), in which R₄ and R₅ combine to form a double bond; R₁ and R₂ combine to form a bond; and R₃ is H). The preparation may involve subjecting the compound of formula (IIC) (e.g., the compound of formula (IIC), in which R₆ is —OP₅) to a phospha-Claisen reaction with CH₃P(O)(OR₆)₂. Phospha-Claisen reaction conditions can be those known in the art. In a non-limiting example, CH₃P(O)(OR₆)₂ can be deprotonated (e.g., by a contact with a strong base) and subsequently contacted with the compound of formula (IIC). The preparation may also involve oxidizing the compound of formula (IIC) (e.g., the compound of formula (IIC), in which R₄ is OH, R₅ is H, and R₆ is CH₂P(O)(OP₆)₂), e.g., by contacting this product with an oxidizing agent capable of oxidizing an alcohol to a carbonyl group.

The compound of formula (IIC) can be prepared from a compound of formula (VIIE), the compound of formula (VIIE) having the following structure:

-   -   where     -   Y₁ is SO₂R₁ and R₁ is optionally substituted non-enolizable         alkyl or optionally substituted aryl, or Y₁ is COOR₁, and R₁ is         optionally substituted alkyl, optionally substituted aryl, or         optionally substituted arylalkyl;     -   R₂ is

-   -    where X₁ is oxo, and R₄ is CHO; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

In a non-limiting example, the compound of formula (IIC) is prepared by reacting the compound of formula (VIIE) (e.g., the compound of formula (VIIE), in which R₂ is

and X₁ is oxo) with a compound of formula (IID), the compound of formula (IID) having the following structure:

-   -   where     -   R₄ is OH or OP₅, and R₅ is H, or R₄ and R₅ combine to form a         double bond;     -   each P₃, P₄, and P₅ is independently a hydroxyl protecting         group; and     -   Y is chloro, bromo, iodo, or trifluoromethanesulfonate.

The compound of formula (VIIE), in which X₁ is oxo, can be reacted with the compound of formula (IID) under the Nozaki-Hiyama-Kishi reaction conditions, as described herein.

C.3-C.4 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbon bond-forming reaction (e.g., catalytic Ring-Closing olefin Metathesis (RCM)) that provides a C.3-C.4 bond in eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate). The general synthetic sequence including RCM that can be used to prepare eribulin or a pharmaceutically acceptable salt thereof (e.g., a mesylate salt) is shown in FIG. 3. As shown in FIG. 3, the non-macrocyclic intermediate in the synthesis of eribulin can be a compound of formula (IIIA):

-   -   where     -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃         combine to form a double bond;         -   or     -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;     -   X₃ is oxo, or X₃ combines with the carbon atom to which it is         attached to form a ketal, a thioketal, or —(CH(OP₅))—, wherein         P₅ is H or a hydroxyl protecting group;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   P₄ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or         -   P₁ and P₂, together with the atoms to which each is             attached, combine to form an aminal or             1,3-oxazolidin-2-one-5-yl.

An intermediate in the synthesis of eribulin can be a compound of formula (IIIB), which can be produced by reacting the compound of formula (IIIA) with an olefin metathesis catalyst (e.g., a ruthenium-carbene complex). The compound of formula (IIIB) has the following structure:

-   -   where all variables are as defined for formula (IIIA).

The catalysts that can be used to convert the compound of formula (IIIA) to the compound of formula (IIIB) can be those known in the art. Olefin metathesis catalysts include Ru-carbene complexes (e.g., Grubbs and Hoveyda-Grubbs catalysts).

The compound of formula (IIIB) can be converted to a compound of formula (ID), from which eribulin or eribulin mesylate can be prepared as described herein. A non-limiting example of the preparation of the compound of formula (ID) from the compound of formula (IIIB) is provided below.

The compound of formula (IIIB), in which X₃, together with the carbon to which it is attached, forms —(CH(OP₅))—, where P₅ is H, can be oxidized to afford the compound of formula (IIIB), in which X₃ is oxo.

Oxidation of the —(CH(OH))— in the compound of formula (IIIB) to give the compound of formula (IIIB), in which X₃ is oxo, can be performed using methods known in the art for oxidation of alcohols to carbonyl groups, e.g., by contacting the compound of formula (IIIB) with an oxidizing agent capable of converting an alcohol to a carbonyl group.

The compound of formula (IIIB) (e.g., the compound of formula (IIIB), in which X₃ is oxo, and P₁ is a hydroxyl protecting group) can be reacted with a hydroxyl protecting group removing agent to afford a compound of formula (ID):

-   -   where     -   each P₃ is H, and X₂ is oxo; or both P₃ groups and X₂, together         with the atoms to which each is attached, combine to form ketal;         and         -   X is O, and P₁ and P₂ are H;         -   or         -   P₁ is H, and X and P₂ combine to form optionally masked             amino.

The conditions for the reaction used in preparing the compound of formula (ID) from the compound of formula (IIIB) can be those allowing for isomerization of a β,γ-enone to an α,β-enone (e.g., including basic or acidic compounds). For example, a hydroxyl protecting group removing agent, such as a fluoride source (e.g., TBAF), can mediate the isomerization of a β,γ-enone to an α,β-enone, while unmasking hydroxyl groups protected with optionally substituted silyl groups.

The compound of formula (ID) (in which X is O, P₁ and P₂ are H, and both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal) can be aminated to afford eribulin, as described herein. Alternatively, the compound of formula (ID) (in which P₁ is H, X and P₂ combine to form a masked amino, and both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal) can be reacted with an amino unmasking agent to afford eribulin, as described herein. Eribulin mesylate can be produced by salification of eribulin, as described herein.

The compound of formula (IIIA) can be prepared from a compound of formula (IIIC):

-   -   where     -   (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃         combine to form a double bond;         -   or     -   (ii) R₁ and R₂ combine to form a bond, and R₃ is H;     -   X₃ is oxo and R₄ is H or OP₆, or X₃ and R₄ combine with the         carbon atom to which they are attached to form an acetal, a         thioacetal, or —CH₂OP₅; where P₅ is H or a hydroxyl protecting         group, and P₆ is an ether hydroxyl protecting group;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   P₄ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or         -   P₁ and P₂, together with the atoms to which each is             attached, combine to form an aminal or             1,3-oxazolidin-2-one-5-yl.

In some embodiments, the preparation of the compound of formula (IIIA) from the compound of formula (IIIC) involves allylating the compound of formula (IIIC) (e.g., the compound of formula (IIIC), in which R₄ is H, and X₃ is oxo, or X₃ and R₄ combine with the carbon atom to which they are attached to form a thioacetal). Allylation of the compound of formula (IIIC) can be performed using conditions known in the art. In a non-limiting example, when X₃ is oxo, and R₄ is H, allylation of the compound of formula (IIIC) can be a nucleophilic allylation (e.g., by contacting the compound of formula (IIIC) with a nucleophilic allylating agent (e.g., allylboron reagent (e.g., allyl boronate or allyl borane), allylstannane, allyl Grignard reagent, allylsilane, or allyl indium). Alternatively, allylation of the compound of formula (IIIC) can be performed using electrophilic allylation (e.g., when X₃ and R₄ combine with the carbon to which they are attached to form a thioacetal). In a non-limiting examples of electrophilic allylation, the compound of formula (IIIC), in which X₃ and R₄ combine with the carbon to which they are attached to form a thioacetal, can be contacted with a strong base followed by an allylic electrophile (e.g., allyl halide or allyl sulfonate).

The preparation of the compound of formula (IIIA) from the compound of formula (IIIC) can also involve reducing the compound of formula (IIIC), in which X₃ is oxo and R₄ is OP₆, with a 1,2-reducing agent to afford a compound of formula (IIIC), in which X₃ is oxo or —(CH(OH))—, and R₄ is H. Formation of the compound of formula (IIIC), in which X₃ is oxo, and R₄ is H, can be direct (e.g., by treating with DIBAL at a temperature between about −70° C. and about −80° C.) or indirect via the compound of formula (IIIC), in which X₃ combines with the carbon atom to which it is attached to form —(CH(OH))—, and R₄ is H. The indirect route to the compound of formula (IIIC), in which X₃ is oxo, and R₄ is H, thus involves first reducing the compound of formula (IIIC), in which X₃ is oxo, and R₄ is OP₆, with a 1,2-reducing agent to give the compound of formula (IIIC), in which X₃ combines with the carbon atom to which it is attached to form —(CH(OH))—, and R₄ is H. The latter compound can be reacted with an oxidizing agent capable of oxidizing an alcohol to a carbonyl group to furnish the compound of formula (IIIC), in which X₃ is oxo, and R₄ is H.

Throughout the oxidation, reduction, and allylation reactions described above, the sensitive functional groups present in the compound of formula (IIIC) can be protected (e.g., R₁ and each P₃ is independently a hydroxyl protecting group) or can be present in an unreactive form (e.g., both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal).

C.19-C.20 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbon bond-forming reaction (e.g., Nozaki-Hiyama-Kishi reaction (NHK)) that provides a C.19-C.20 bond in eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate). The general synthesis sequence including NHK that can be used to prepare eribulin or a pharmaceutically acceptable salt thereof (e.g., a mesylate salt) is shown in FIG. 4. As shown in FIG. 4, the non-macrocyclic intermediate in the synthesis of eribulin can be a compound of formula (IVA):

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   a designates R stereogenic center, and Z is a sulfonate,         chloride, bromide, or iodide; or a designates S stereogenic         center, and Z is OR₁, wherein R₁ is a hydroxyl protecting group;     -   (i) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine to         form a double bond;     -   or     -   (ii) R₂ and R₃ combine to form a bond, and R₄ is H;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

An intermediate in the synthesis of eribulin can be a compound of formula (IVB), which can be produced by subjecting the compound of formula (IVA) to Nozaki-Hiyama-Kishi reaction conditions (e.g., by reacting with a Cr(II) salt and a Ni(II) salt). The compound of formula (IVB) has the following structure:

-   -   where P₁, P₂, P₃, X, and X₂ are as defined for compound of         formula (IVB);         -   a designates R stereogenic center, b designates S             stereogenic center, Z is a sulfonate, chloride, bromide, or             iodide;         -   or         -   a designates S stereogenic center, b designates R             stereogenic center, and Z is OR₁,         -   wherein R₁ is a hydroxyl protecting group.

Nozaki-Hiyama-Kishi reaction conditions that may be used to prepare the compound of formula (IVB) from the compound of formula (IVA) can be those known in the art. Nozaki-Hiyama-Kishi reaction on the compound of formula (IVA) can include reacting the compound of formula (IVA) with a Cr(II) salt and a Ni(II) salt. Ancillary ligands can be used in combination with the metal salts. In a non-limiting example, a substituted 1,10-phenanthroline can be used in combination with a Ni(II) salt. Chiral ancillary ligands can be used to render the reaction stereoselective. In a non-limiting example, chiral N-(dihydrooxazolyl-phenyl)-sulfonamides can be used with a Cr(II) salt to control the stereochemistry of the carbonyl carbon, to which a vinyl nucleophile is added in the course of Nozaki-Hiyama-Kishi reaction.

The compound of formula (IVB) can be converted to a compound of formula (ID), from which eribulin or erinulin mesylate can be prepared, as described herein. A non-limiting exemplary reaction sequence from the compound of formula (IVB) to the compound of formula (ID) is provided below.

The compound of formula (IVB) can be converted to a compound of formula (ID) directly or via an intermediate of formula (IVC). Thus, the compound of formula (IVB), in which Z is an ester, a designates S stereogenic center, b designates R stereogenic center, can be converted to the compound of formula (IVC), e.g., by reacting with a sulfonyl electrophile, such as a sulfonyl chloride or a sulfonyl anhydride.

-   -   where     -   a designates S stereogenic center;     -   b designates R stereogenic center;     -   Z is an ester;     -   (i) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine to         form a double bond;     -   or     -   (ii) R₂ and R₃ combine to form a bond, and R₄ is H;     -   R₅ is sulfonyl;     -   each P₃ is independently a hydroxyl protecting group, and X₂ is         oxo; or both P₃ groups and X₂, together with the atoms to which         each is attached, combine to form ketal;     -   and         -   X is O, and             -   each of P₁ and P₂ is independently a hydroxyl protecting                 group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   P₁ is a hydroxyl protecting group, and X and P₂ combine to             form optionally masked amino.

The preparation of the compound of formula (ID) from the compound of formula (IVC) can involve reacting the compound of formula (IVC) with a C₁₋₆ alkoxide. The compound of formula (ID) has the following structure:

-   -   where     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal; and         -   X is O, and             -   each of P₁ and P₂ is independently a hydroxyl protecting                 group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   P₁ is a hydroxyl protecting group, and X and P₂ combine to             form optionally masked amino.

The compound of formula (IVB) (in which Z is a sulfonate, chloride, bromide, or iodide, a designates R stereogenic center, b designates S stereogenic center, R₂ and R₃ combine to form a bond, and R₄ is H) can be converted to the compound of formula (ID) directly, e.g., upon isolation from the Nozaki-Hiyama-Kishi reaction mixture (e.g., by treatment with a base) or by contacting a mixture containing the product of the Nozaki-Hiyama-Kishi reaction with silica gel.

The compound of formula (ID) (e.g., the compound of formula (ID) in which P₁ is a hydroxyl protecting group) can be reacted with a hydroxyl protecting group removing agent to afford:

-   -   where     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

The compound of formula (ID) (in which X is O, P₁ and P₂ are H, and both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal) can be aminated to afford eribulin, as described herein. Alternatively, the compound of formula (ID) (in which P₁ is H, X and P₂ combine to form a masked amino, and both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal) can be reacted with an amino unmasking agent to afford eribulin, as described herein. Eribulin mesylate can be produced by salification of eribulin, as described herein.

The compound of formula (IVA) can be prepared from the compound of formula (IVD):

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   Y₁ is H, COOR₆, or SO₂R₆, where, when Y₁ is COOR₆, R₆ is         optionally substituted alkyl, optionally substituted aryl, or         optionally substituted arylalkyl, and, when Y₁ is SO₂R₆, R₆ is         optionally substituted aryl or optionally substituted         non-enolizable alkyl;     -   Z is an ester, a sulfonate, chloride, bromide, or iodide;     -   (i) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine to         form a double bond;     -   or     -   (ii) R₂ and R₃ combine to form a bond, and R₄ is H;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   X₃ is oxo, or X₃ combines with the carbon atom to which it is         attached to form —(CH(OH))—; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

In some embodiments, the preparation of the compound of formula (IVA) involves oxidizing the compound of formula (IVD), in which X₃ is —(CH(OH))—, and/or P₄ is H, e.g., by reacting with an oxidizing agent capable of oxidizing an alcohol to a carbonyl group. The preparation of the compound of formula (IVA) can also involve performing a decarboxylation or desulfonylation reaction on the compound of formula (IVA), in which Y₁ is COOR₆ (decarboxylation) or SO₂R₆ (desulfonylation).

In certain embodiments, the compound of formula (IVD) can be prepared from a compound of formula (IVE) and the compound of formula (VIIE):

-   -   or a salt thereof,     -   where all variables are as defined in formula (IVD).

The compound of formula (IVE) can have the following structure:

-   -   where     -   (a1) R₇ and R₈ combine to form a bond, and R₉ is H;     -   or     -   (a2) R₇ is H or a hydroxyl protecting group, and R₈ and R₉         combine to form a double bond;     -   X₃ is oxo, and R₁₀ is H or —OP₅, where P₅ is H or an ether         hydroxyl protecting group; and the remaining variables are as         defined in formula (IVD).

In particular embodiments, the compound of formula (IVD) is prepared by reacting the compound of formula (IVE) (e.g., the compound of formula (IVE), in which X is oxo) with the compound of formula (VIIE) which was pretreated with a strong base.

C.0-C.1 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbon bond-forming reaction (e.g., Dieckmann reaction) that provides a C.0-C.1 bond in eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate). The general synthetic sequence including the Dieckmann reaction that can be used to prepare eribulin or a pharmaceutically acceptable salt thereof (e.g., a mesylate salt) is shown in FIG. 5. As shown in FIG. 5, the non-macrocyclic intermediate in the synthesis of eribulin can be:

-   -   where     -   Y is SO₂R₁ or COOR₁, where, when Y is SO₂R₁, R₁ is optionally         substituted aryl or optionally substituted non-enolizable alkyl,         and when Y is COOR₁, R₁ is optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo, or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   R₂ is optionally substituted alkyl, optionally substituted         arylalkyl, or optionally substituted aryl; and     -   X is O, and         -   each of P₁ and P₂ is independently a hydroxyl protecting             group,         -   or         -   P₁ and P₂, together with the atoms to which each is             attached, combine to form a cyclic protected diol;     -   or     -   X is N, and         -   P₁ is H or a hydroxyl protecting group, and X and P₂ combine             to form optionally masked amino;         -   or         -   P₁ and P₂, together with the atoms to which each is             attached, combine to form an aminal or             1,3-oxazolidin-2-one-5-yl.

An intermediate in the synthesis of eribulin can be a compound of formula (VB), which can be produced from the compound of formula (VA) using Dieckmann reaction. The compound of formula (VB) has the following structure:

-   -   where P₁, P₂, P₃, X, X₂, and Y are as defined for compound of         formula (VA); and     -   (i) R₃ is H, R₄ is optionally substituted C₁₋₆ alkyl ether, and         R₅ is H;     -   (ii) R₅ is H, and R₃ and R₄ combine to form a double bond;     -   or     -   (iii) R₃ is H, and R₄ and R₅ combine to form a bond

The reaction conditions that can be used to convert the compound of formula (VA) into the compound of formula (VB) include those known in the art for the Dieckmann reaction or Claisen condensation. In particular, the compound of formula (VA) can be contacted with a strong base (e.g., a C₄₋₆ alkoxide) to afford the compound of formula (VB). The compound of formula (VB)(i) or (VB)(ii) can be converted to the compound of formula (VB)(iii) prior to the next step by contacting the compound of formula (IIB)(i) or (VB)(ii) with aqueous bicarbonate (e.g., during a work up of the Dieckmann reaction mixture) or with silica gel (e.g., by purification of the compound of formula (VB) by silica gel chromatography).

The compound of formula (VB) can be converted to the compound of formula (ID), from which eribulin or eribulin mesylate can be produced as described herein. For example, the reaction sequence from the compound of formula (VB) to the compound of formula (ID) can include (i) a desulfonylation or a decarboxylation reaction and (ii) reactions with hydroxyl protecting group removing agent or an amino unmasking agent. The conditions for the decarboxylation reaction can be those known in the art, e.g., Krapcho decarboxylation or a sequence including deprotection (converting R₁ to H) and protodecarboxylation. The conditions for the desulfonylation reaction can be those known in the art. For example, the desulfonylation reaction can include contacting the compound of formula (IIB), in which Y is SO₂R₁, with an electron-transferring reducing agent (e.g., SmI₂; Cr(III) salt and Mn(0); or Mg(0)). For exemplary desulfonylation conditions, see WO 2009/064029.

The compound of formula (ID) (e.g., the compound of formula (ID) in which P₁ is a hydroxyl protecting group) can be reacted with a hydroxyl protecting group removing agent to afford:

-   -   where     -   both P₃ groups and X₂, together with the atoms to which each is         attached, combine to form ketal; and         -   X is O, and each of P₁ and P₂ is H,         -   or

P₁ is H, and X and P₂ combine to form optionally masked amino.

The compound of formula (ID) (in which X is O, P₁ and P₂ are H, and both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal) can be aminated to afford eribulin, as described herein. Alternatively, the compound of formula (ID) (in which P₁ is H, X and P₂ combine to form a masked amino, and both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal) can be reacted with an amino unmasking agent to afford eribulin, as described herein. Eribulin mesylate can be produced by salification of eribulin, as described herein.

The compound of formula (VA) can be prepared from the compound of formula (VIIE):

-   -   where     -   Y is SO₂R₁ or COOR₁, where, when Y is SO₂R₁, R₁ is optionally         substituted aryl or optionally substituted non-enolizable alkyl,         and when Y is COOR₁, R₁ is optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;     -   P₃ is H or a hydroxyl protecting group; and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or         -   P₁ and P₂, together with the atoms to which each is             attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

The preparation of the compound of formula (VA) from the compound of formula (VIIE) can involve oxidizing the compound of formula (VIIE), in which P₃ is H, and subjecting the product to the Nozaki-Hiyama-Kishi reaction with a compound of formula (VC):

-   -   where     -   R₂ is optionally substituted alkyl, optionally substituted         arylalkyl, or optionally substituted aryl;     -   Y₁ is chloro, bromo, iodo, or trifluoromethanesulfonate; and     -   each P₃ and P₄ is independently a hydroxyl protecting group.

Further reaction with a hydroxyl protecting group removing agent and a reaction with a Brønsted acid can provide the compound of formula (VA).

C.26-C.27 Bond-Forming Macrocyclization

The macrocyclization reaction of the invention can be a carbon-carbon bond-forming reaction (e.g., Nozaki-Hiyama-Kishi reaction (NHK)) that provides a C.26-C.27 bond in eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate). The general synthesis sequence including NHK that can be used to prepare eribulin or a pharmaceutically acceptable salt thereof (e.g., a mesylate salt) is shown in FIG. 6. As shown in FIG. 6, the non-macrocyclic intermediate in the synthesis of eribulin can be a compound of formula (VIA):

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine         to form a double bond, each P₃ is independently H or a hydroxyl         protecting group, and X₂, together with the carbon to which it         is attached, forms a carbonyl or —(CH(OR₆))—, where R₆ is H or a         hydroxyl protecting group;     -   or     -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and         -   each P₃ is independently H or a hydroxyl protecting group,             and X₂, together with the carbon to which it is attached,             forms a carbonyl or —(CH(OR₆))—;         -   or         -   both P₃ groups and X₂, together with the atoms to which each             is attached, combine to form ketal;     -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to         form a bond;     -   or     -   (b2) Z and R₂ combine to form a double bond, and R₁ is H or a         hydroxyl protecting group;     -   and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

An intermediate in the synthesis of eribulin can be a compound of formula (VIB), which can be produced by subjecting the compound of formula (VIA) to Nozaki-Hiyama-Kishi reaction conditions (e.g., by reacting with a Cr(II) salt and a Ni(II) salt). The compound of formula (VIB) has the following structure:

-   -   where all variables are as defined for compound of formula         (VIA); and     -   P₄ is H or a hydroxyl protecting group.

Nozaki-Hiyama-Kishi reaction conditions are as described above.

The compound of formula (VIC) can be prepared from the compound of formula (VIB):

-   -   where all variables are as defined for compound of formula         (VIB).

The synthesis of the compound of formula (VIC) can involve Vasella fragmentation, reaction(s) with one or more hydroxyl protecting agents, a nucleophilic cyclization reaction, and oxidation reactions, e.g., before or after the NHK step (i.e., the reaction affording the compound of formula (VIB)).

The compound of formula (VIC) can be converted to the compound of formula (ID), from which eribulin or eribulin mesylate can be prepared as described herein. In a non-limiting example, the compound of formula (VIC) (e.g., the compound of formula (VIC) in which each of P₁, P₂, P₃, and R₃ is a hydroxyl protecting group, X₂ is oxo, and R₄ and R₅ combine to form a double bond) can be converted to a compound of formula (ID) through a synthesis involving reacting the compound of formula (VIC) with a hydroxyl protecting group removing agent. The synthesis may further involve a reaction with a Brønsted acid (e.g., a Brønsted acid having a pKa of 5±3) after the reaction of the compound of formula (VIC) with a hydroxyl protecting group removing agent.

The compound of formula (ID) (e.g., the compound of formula (ID) in which P₁ is a hydroxyl protecting group) can be reacted with a hydroxyl protecting group removing agent:

-   -   where     -   both P₃ groups and X₂, together with the atoms to which each is         attached, combine to form ketal; and         -   X is O, and each of P₁ and P₂ is H,         -   or         -   P₁ is H, and X and P₂ combine to form optionally masked             amino.

The compound of formula (ID) (in which X is O and P₁ and P₂ are H) can be aminated to afford eribulin, as described herein. Alternatively, the compound of formula (ID) (in which P₁ is H and X and P₂ combine to form a masked amino) can be reacted with an amino unmasking agent to afford eribulin, as described herein. Eribulin mesylate can be produced by salification of eribulin, as described herein.

The compound of formula (VIA) can be prepared from the compound of formula (VID):

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   Y₁ is H, SO₂R₇, or COOR₇, where, when Y₁ is COOR₇, R₇ is         optionally substituted alkyl, optionally substituted aryl, or         optionally substituted arylalkyl, and, when Y₁ is SO₂R₇, R₇ is         optionally substituted aryl or optionally substituted         non-enolizable alkyl;     -   X₃ is oxo, or X₃ combines with the carbon to which it is         attached to form —(CH(OR₆))—;     -   P₅ is H or a hydroxyl protecting group;     -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine         to form a double bond, each P₃ is independently H or a hydroxyl         protecting group, and X₂, together with the carbon to which it         is attached, forms a carbonyl or —(CH(OR₆))—;     -   or     -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and         -   each P₃ is independently H or a hydroxyl protecting group,             and X₂, together with the carbon to which it is attached,             forms a carbonyl or —(CH(OR₆))—;         -   or         -   both P₃ groups and X₂, together with the atoms to which each             is attached, combine to form ketal;     -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to         form a bond;     -   or     -   (b2) Z and R₂ combine to form a double bond, and R₁ is a         hydroxyl protecting group;     -   and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl;     -   where each R₆ is independently H or a hydroxyl protecting group.

The preparation of the compound of formula (VIA) can involve oxidizing the compound of formula (VID) (e.g., the compound of formula (VID), in which P₅ is H or a hydroxyl protecting group, and/or X₃ combines with the carbon to which it is attached to form —(CH(OR₆))—), e.g., by reacting with an oxidizing agent capable of oxidizing hydroxyl to a carbonyl group. The mixture containing the oxidizing agent can also act as a hydroxyl protecting removing agent. The preparation may further involve a desulfonylation reaction (when Y₁ is COOR₇) or a desulfonylation (when Y₁ is SO₂R₇), as described herein.

The compound of formula (VID) can be formed by reacting the compound of formula (VIE) with the compound of formula (VIF). The compound of formula (VIE) can have the following structure:

-   -   where     -   R₉ is H or —OR₉, where R₉ is H or an ether hydroxyl protecting         group; and     -   the remaining variables are as defined in formula (VID).

The compound of formula (VIF) can have the following structure

-   -   where all variables are as defined in formula (VID).

Allene-Prins Reaction in the Preparation of C.20-C.35, C.16-C.35, and C.14-C35 Fragments of Eribulin

The invention further features a method of preparing a fragment of eribulin (e.g., C.20-C.35, C.16-C.35, and C.14-C35 fragments), which can be an intermediate in the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate). The advantages of the process relative to the current synthesis of C.14-C.35, C.16-C.35, and C.20-C.35 fragments of eribulin include non-metal mediated assembly that does not employ a C.23 leaving group. Additionally, the process obviates the need for a chiral ligand. The method involves performing an allene-Prins reaction on a compound of formula (VIIA), a compound of formula (VIIB), and R₃OH to afford the intermediate in the synthesis of eribulin,

-   -   where R₃ is an optionally substituted acyl;     -   where the compound of formula (VIIA) has the following         structure:

-   -   where     -   Y₁ is SO₂R₁, or COOR₁, and R₁ is optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;     -   X₁ is O, or X₁, together with the carbon to which the X₁ groups         are attached, forms a cyclic acetal;         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl; and     -   where the compound of formula (VIIB) has the following         structure:

-   -   where         -   P₃ is H or a hydroxyl protecting group; each P₄ is             independently a hydroxyl protecting group, or both P₄             groups, together with the atoms to which each is attached,             combine to form a cyclic protected diol; and R₄ is H or             —CH₂X₂CH₂CH═CH₂, where X₂ is O, —CH₂—, or NP₅, where P₅ is             sulfonyl;     -   and where the intermediate in the synthesis of eribulin is a         compound of formula (VIIC):

-   -   where a designates R stereogenic center or S stereogenic center.

The reaction conditions that can be used to prepare the compound of formula (VIIC) using allene-Prins reaction are those known in the art for Prins reaction and can include reacting the compound of formula (VIIA), the compound of formula (VIIB), and R₃OH with a Lewis acid (e.g., boron trifluoride or a solvate thereof).

The compound of formula (VIIC) can be subjected to allylic reducing conditions to afford a compound of formula (VIID):

-   -   Y₁ is SO₂R₁ or COOR₁, and R₁ is optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;

-   -   -   where         -   P₃ is H or a hydroxyl protecting group; each P₄ is             independently a hydroxyl protecting group, or both P₄             groups, together with the atoms to which each is attached,             combine to form a cyclic protected diol; and R₄ is H or             —CH₂X₂CH₂CH═CH₂, where X₂ is O, —CH₂—, or NP₅, where P₅ is             sulfonyl;         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;             -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl.

The compound of formula (VIIB) can be prepared from the compound of formula (VIIF):

-   -   where     -   Y is chloro, bromo, iodo, or sulfonate; and

-   -   -   where         -   P₃ is a hydroxyl protecting group; each P₄ is independently             a hydroxyl protecting group, or both P₄ groups, together             with the atoms to which each is attached, combine to form a             cyclic protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, where             X₂ is O, —CH₂—, or NP₅, where P₅ is sulfonyl.

The compound of formula (VIIF) can be reacted with a Pd(0) complex, which can be prepared in situ, and a base to afford the compound of formula (VIIB). Alternatively, the compound of formula (VIIB) can be reacted with a base directly (e.g., N-methylimidazole) to afford the compound of formula (VIIB).

The compound of formula (VIIB) can be prepared from a compound of formula (VIIG):

-   -   where     -   Y is chloro, bromo, iodo, or sulfonate; and

-   -   -   where         -   P₃ is a hydroxyl protecting group; each P₄ is independently             a hydroxyl protecting group, or both P₄ groups, together             with the atoms to which each is attached, combine to form a             cyclic protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, where             X₂ is O, —CH₂—, or NP₅, where P₅ is sulfonyl.

The compound of formula (VIIG) can be reacted with a methylcuprate (I) salt (e.g., lithium methyl-cyanocuprate) to form the compound of formula (VIIB).

The compound of formula (VIIB) can be prepared from a compound of formula (VIIH):

-   -   where     -   P₃ is a hydroxyl protecting group; each P₄ is independently a         hydroxyl protecting group, or both P₄ groups, together with the         atoms to which each is attached, combine to form a cyclic         protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, where X₂ is O,         —CH₂—, or NP₅, where P₅ is sulfonyl.

The compound of formula (VIIH) can be reacted with a sulfonyl hydrazide (e.g., mesitylsulfonyl hydrazide) and a base (e.g., an organic base having a pKa from 10 to 14).

C.1-C.15 Fragment

The invention also features a C.1-C.15 fragment of eribulin, which can be used in the synthesis of eribulin. The C.1-C.15 fragment can be prepared from the waste stream in the synthesis or eribulin disclosed in WO 2005/118565 (see preparation of the intermediate ER-806055). The C.1-C.15 fragment can be a compound of formula (VIIIL):

-   -   where     -   R₁ is H or —CH₂OP₄;     -   X₂ is oxo, or X₂, together with the carbon to which it is         attached, forms a ketal or —(CH(OP₆))—;     -   each of P₁ and P₄, when present, is independently H or a         hydroxyl protecting group, or P₁ and P₄, when present, together         with the atoms to which each is attached, combine to form a         cyclic protected diol; and     -   each of P₂, P₅, and P₆ is independently H or a hydroxyl         protecting group.

The method of preparing the C.1-C.15 fragment can involve:

-   -   (A) cleaving the double bond in a compound of formula (VIIIA) to         afford a compound of formula (VIIIB), the compound of formula         (VIIIA) having the structure:

-   -   where         -   X₁ is oxo, or X₁, together with the carbon atom to which it             is attached, forms a ketal or —(CH(OP₃))—, wherein P₃ is H             or a hydroxyl protecting group;         -   R₁ is H or —CH₂OP₄;         -   each of P₁, P₂, and P₄ is independently a hydroxyl             protecting group, or         -   P₁ and P₄, together with the atoms to which each is             attached, combine to form a cyclic protected diol; and     -   the compound of formula (VIIIB) having the structure:

-   -   (B) reacting the compound of formula (VIIIB) with a compound of         formula (VIIIB-a) to afford a compound of formula (VIIIC):

-   -   where R₂ is H or —CH₂CH₂OP₅, and P₅ is a hydroxyl protecting         group;     -   and the compound of formula (VIIIB-a) has the following         structure:

-   -   (C) reacting the compound of formula (VIIIC) with a dehydrating         agent to afford a compound of formula (VIIID):

-   -   (D) reacting the compound of formula (VIIID) with a         dihydroxylating agent to afford a compound of formula (VIIIE):

-   -   (E) preparing a compound of formula (VIIIF) through a reaction         sequence comprising reacting the compound of formula (VIIIE)         with N-bromosuccinimide to afford a first intermediate, and (a),         when R₂ is —CH₂CH₂OP₅, contacting said first intermediate with a         reducing agent (e.g., a hydrosilane and a Brønsted or Lewis         acid), or (b), when R₂ is H, reacting said first intermediate         with an acylating agent (e.g., carboxylic acid anhydride) to         afford a second intermediate, and allylating said second         intermediate to afford a compound of formula (VIIIF):

-   -   where Z is an ester or —OP₇, where P₇ is H or a hydroxyl         protecting group, and R₃ is —CH₂CH₂OP₅ or —CH₂CH═CH₂;     -   (F) reacting the compound of formula (VIIIF) with a 1,4-reducing         agent to afford a compound of formula (VIIIG):

-   -   (G) forming a compound of formula (VIIIH) through a reaction         sequence comprising reacting the compound of formula (VIIIG)         with a Brønsted acid and Y—H, wherein Y is optionally         substituted C₁₋₆ alkyl, the compound of formula (VIIIH) having         the following structure:

-   -   where Y is optionally substituted C₁₋₆ alkyl ether; R₃ is         —CH₂CH₂OP₅; X₂ is oxo, or X₂, together with the carbon to which         it is attached, forms a ketal or —(CH(OP₆))—, where P₆ is a         hydroxyl protecting group;     -   (H) replacing P₂ in the compound of formula (VIIIH) with         —Si(R₄)₂H to afford a compound of formula (VIIIJ):

-   -   where each R₄ is independently optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;     -   (I) reacting the compound of formula (VIIIJ) with a Lewis acid         to afford a compound of formula (VIIIK):

-   -   where Y₂ is fluoro, chloro, or bromo;     -   and     -   (J) reacting the compound of formula (VIIIK) with a hydroxyl         protecting group removing agent and then reacting with a         hydroxyl protecting agent to afford a compound of formula         (VIIIL):

-   -   where P₂ is a hydroxyl protecting group.

Compounds

The present invention also provides compounds that can be used in the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate), e.g., the compounds of formula (IA), (IB), (IC), (ID), (IE), (IIA), (IIB), (IIC), (IIIA), (IIIB), (IIIC), (IVA), (IVB), (IVC), (IVD), (VA), (VB), (VIA), (VIB), (VIC), (VID), (VIIB), (VIIC), (VIIF), (VIIG), (VIIH), or (VIIIL), or a salt thereof. The present invention also includes a compound of formula (VIIE):

-   -   or a salt thereof,     -   where     -   Y₁ is SO₂R, or COOR₁, and R₁ is optionally substituted alkyl,         optionally substituted aryl, or optionally substituted         arylalkyl;

-   -   -   where X₁ is oxo, or X₁ combines with the carbon atom to             which it is attached to form —(CH(OP₃))—; each P₃ is             independently H or a hydroxyl protecting group; each P₄ is             independently H or a hydroxyl protecting group, or both P₄             groups, together with the atoms to which each is attached,             combine to form a cyclic protected diol; R₄ is H, CHO, or             —CH₂X₂CH₂CH═CH₂, where X₂ is O, —CH₂—, or NP₅, where P₅ is             sulfonyl; and

    -   X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂         combine to form optionally masked amino; or P₁ and P₂, together         with the atoms to which each is attached, combine to form an         aminal or 1,3-oxazolidin-2-one-5-yl.

The present invention includes a compound of formula (IVE):

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   Z is an ester, a sulfonate, chloride, bromide, or iodide;     -   each P₃ is independently H or a hydroxyl protecting group, and         X₂ is oxo; or both P₃ groups and X₂, together with the atoms to         which each is attached, combine to form ketal;     -   (a1) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine         to form a double bond;     -   or     -   (a2) R₂ and R₃ combine to form a bond, and R₄ is H;     -   (b1) R₇ and R₈ combine to form a bond, and R₉ is H;     -   or     -   (b2) R₇ is H or a hydroxyl protecting group, and R₈ and R₉         combine to form a double bond; and     -   (c1) X₃ is oxo, and R₁₀ is H or —OP₅, where P₅ is H or an ether         hydroxyl protecting group;     -   or     -   (c2) X₃ and R₁₀ combine with the carbon atom to which they are         attached to form an acetal or —CH₂OP₆, where P₆ is H or a         hydroxyl protecting group.

The present invention includes a compound of formula (VIE):

-   -   where     -   Y is iodide, bromide, or trifluoromethanesulfonate;     -   (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine         to form a double bond, each P₃ is independently H or a hydroxyl         protecting group, and X₂, together with the carbon to which it         is attached, forms a carbonyl or —(CH(OR₆))—;     -   or     -   (a2) R₃ and R₄ combine to form a bond, R₅ is H, and         -   each P₃ is independently H or a hydroxyl protecting group,             and X₂, together with the carbon to which it is attached,             forms a carbonyl or —(CH(OR₆))—;         -   or         -   both P₃ groups and X₂, together with the atoms to which each             is attached, combine to form ketal;     -   (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to         form a bond;     -   or     -   (b2) Z and R₂ combine to form a double bond, and R₁ is H or a         hydroxyl protecting group;     -   (c1) X₃ is oxo, and R₈ is H or —OR₉, where R₉ is H or a hydroxyl         protecting group;     -   (c2) X₃ and R₈ combine with the carbon to which they are         attached to form an acetal;     -   (c3) X₃ and R₈ combine with the carbon to which they are         attached to form —CH₂OR₆;     -   or     -   (c4) X₃ and R₈ combine with the carbon to which they are         attached to form —CN;     -   and         -   X is O, and             -   each of P₁ and P₂ is independently H or a hydroxyl                 protecting group,             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form a cyclic protected diol;         -   or         -   X is N, and             -   P₁ is H or a hydroxyl protecting group, and X and P₂                 combine to form optionally masked amino;             -   or             -   P₁ and P₂, together with the atoms to which each is                 attached, combine to form an aminal or                 1,3-oxazolidin-2-one-5-yl;     -   where each R₆ is independently H or a hydroxyl protecting group.

Amination

Amination conditions can be those known in the art. In a non-limiting example, C.35 hydroxyl in the compound of formula (IC) (e.g., a compound of formula (IC) in which each of P₁ and P₂ is H and X is O) can be sulfonylated (e.g., by a reaction with a sulfonyl anhydride or a sulfonyl chloride) and reacted with a nitrogen source (e.g., ammonia, azide, sulfamic acid, urea (H₂NCONH₂), or thiourea (H₂NCSNH₂)) to afford eribulin or a pharmaceutically acceptable salt thereof upon optional unmasking of the amino group (if the nitrogen source was azide, urea, or thiourea). In another non-limiting example, C.35 hydroxyl in the compound of formula (IC) (e.g., a compound of formula (IC) in which P₁ is a hydroxyl protecting group, and P₂ is H and X is O) can be halogenated (e.g., by Appel reaction or a reaction with thionyl chloride, sulfuryl chloride, phosphorus(III) chloride, or phosphorus(V) oxychloride) and reacted with a nitrogen source (e.g., ammonia, azide, sulfamic acid, a phthalimide salt, urea (H₂NCONH₂), or thiourea (H₂NCSNH₂)) to afford eribulin or a pharmaceutically acceptable salt thereof upon optional unmasking of the amino group (if the nitrogen source was azide, a phthalimide salt, urea, or thiourea). In yet another non-limiting example, C.35 hydroxyl in the compound of formula (IC) (e.g., a compound of formula (IC) in which P₁ is a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino) can be reacted with a hydroxyl protecting group removing agent to afford eribulin (when X and P₂ combine to form unmasked amino) or, when X and P₂ combine to form a masked amino, either before or after the treatment with the hydroxyl protecting group removing agent, the compound of formula (IC) can be reacted with an amino unmasking agent to afford eribulin. Amino unmasking agents are further described herein. The amination reaction can provide a pharmaceutically acceptable salt of eribulin directly. Alternatively, the amination reaction can provide eribulin in a free base form. A pharmaceutically acceptable salt of eribulin can be prepared from eribulin through a salification reaction as described herein.

Salification

Salification reaction conditions are known in the art. Salification of eribulin can afford a pharmaceutically acceptable salt of eribulin (e.g., eribulin mesylate). In particular, salification reaction can involve contacting eribulin with a Brønsted acid (e.g., a pharmaceutically acceptable Brønsted acid (e.g., methanesulfonic acid)) to afford a pharmaceutically acceptable salt of eribulin (e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed.: Stahl and Wermuth, Wiley-VCH/VHCA, Weinheim/Zurich, 2002). Pharmaceutically acceptable salts of eribulin, e.g., eribulin mesylate, can be formed by methods known in the art, e.g., in situ during the final isolation and purification of the compound or separately by reacting the free base group with a suitable organic acid. In one example, eribulin is treated with a solution of MsOH and NH₄OH in water and acetonitrile. The mixture is concentrated. The residue is dissolved in DCM-pentane, and the solution is added to anhydrous pentane. The resulting precipitate is filtered and dried under high vacuum to provide eribulin mesylate

Oxidizing Agents Capable of Converting an Alcohol to a Carbonyl Group

Oxidizing agents capable of converting an alcohol to a carbonyl group are known in the art. Non-limiting examples of these oxidizing agents include Dess-Martin periodinane, TEMPO (in the presence of bleach or BAIB), a dimethylsulfonium compound (e.g., dimethylchlorosulfonium chloride), aluminum trialkoxide with an excess of a ketone (e.g., acetone), and catalytic tetrapropylammonium perruthenate (TPAP) (in the presence of N-methylmorpholine oxide). The dimethylsulfonium compound can be prepared in situ under the conditions known for Parikh-Doering oxidation, Swern oxidation, Corey-Kim oxidation, or Pfitzner-Moffatt oxidation. An oxidation reaction of an alcohol to a carbonyl group (e.g., a ketone) can be performed using aluminum trialkoxide and an excess of a ketone (e.g., acetone) under the conditions known in the art for Oppenauer oxidation. Allylic and benzylic alcohols can also be oxidized with MnO₂.

Reducing Agents

Reducing agents that can be used in the methods of the invention are those known in the art. A reducing agent can be an electron-transfer reducing agent, a metal hydride, or a metalloid hydride. Non-limiting examples of electron-transfer reducing agent include alkali metals in oxidation state (0), alkali earth metals in oxidation state (0), alkali arenides, lanthanide (II) salts (e.g., SmI₂), Zn(0), Fe(0), and Mn(0).

Non-limiting examples of metal hydrides and metalloid hydrides include boron hydride compounds (e.g., NaBH₄, LiBH₄, LiB(Et)₃H, selectrides (e.g., L-selectride), and boranes (e.g., 9-BBN and alpine borane)), aluminum hydride compounds (e.g., LiAlH₄, Red-Al®, and alanes (e.g., DIBAL)), hydrosilanes (e.g., PMHS and Ph₂SiH₂), hydrostannanes (e.g., Bu₃SnH), copper hydride complexes (e.g., Stryker's reagent), palladium hydride complexes, platinum hydride complexes, iridium hydride complexes, rhodium hydride complexes, and ruthenium hydride complexes. Reducing agents can be formed in situ, e.g., a copper hydride complex can be formed by a reaction of a copper salt with, e.g., a boron hydride compound or a hydrosilane. Thus, some reducing reagents (e.g., boron hydride compounds, hydrosilanes, and hydrostannanes) can be used in combination with a catalytic quantity of a metal salt (e.g., Cu, Pd, Pt, Ir, Rh, or Ru salt). Alternatively, catalytic reducing agents can be metal salts (e.g., aluminum isopropoxide or a ruthenium complex) in combination with an alcohol, which undergo transfer hydrogenation of carbonyl-containing compounds without intermediacy of a metal hydride. Non-limiting examples of transfer hydrogenation reactions include Meerwein-Ponndorf-Verley reduction (e.g., using aluminum isopropoxide/isopropanol) and Ru-catalyzed transfer hydrogenation (e.g., Hashiguchi et al., J. Am. Chem. Soc., 117:7562-7563, 1995).

When a substrate is an α,β-unsaturated carbonyl compound (e.g., an α,β-enone), a reducing agent can be a 1,2-reducing agent or a 1,4-reducing agent. For example, a reaction between an α,β-unsaturated carbonyl compound and a 1,2-reducing agent can afford, e.g., an allylic alcohol (or an allylic amine, if the starting compound is an enamide), whereas a reaction between an α,β-unsaturated carbonyl compound and a 1,4-reducing agent can afford an α,β-saturated compound and can leave the carbonyl group intact after work up of the reaction mixture. Non-limiting examples of 1,2-reducing agents include metal hydrides and metalloid hydrides, e.g., aluminum hydride compounds, boron hydride compounds (e.g., CeCl₃ with NaBH₄), and ruthenium hydride complexes. Non-limiting examples of 1,4-reducing agents include boron hydride compounds, hydrostannanes, copper hydride complexes (e.g., Stryker's reagent), palladium hydride complexes, platinum hydride complexes, iridium hydride complexes, rhodium hydride complexes, and ruthenium hydride complexes.

A compound having an allylic leaving group (e.g., a carboxylate, a halide, or a sulfonate) can be treated with an allylic reducing agent to replace the leaving group with a hydrogen atom. A non-limiting example of allylic reducing agent is a palladium salt in combination with a formic acid salt (e.g., trialkylammonium formate).

Masked Amines and Amine Unmasking Agents

The compounds used in the methods of the invention can contain a masked or unmasked amine (e.g., at C.35 carbon of the structure of eribulin). An unmasked amine is —NH₂. Amine can be masked using methods known in the art, e.g., by protecting amine with an N-protecting group. Alternatively, amine can be masked as a nitrogen-containing moiety, which can be reacted with an amine unmasking agent to afford an amine. Non-limiting examples of the nitrogen-containing moieties include azide, an imide (e.g., phathalimide), Amine unmasking agents can be those known in the art for removing N-protecting groups from amines. In a non-limiting example, a Boc group can be removed using amine unmasking agents known in the art, e.g., a Brønsted acid (e.g., HCl in 1,4-dioxane or trifluoroacetic acid). When amine is masked as azide, the amine can be unmasked by subjecting the compound containing the masked amine to Staudinger reaction conditions (e.g., by contacting with a phosphine, such as trialkylphosphine, dialkylarylphosphine, alkyldiarylphosphine, or triarylphosphine) or by reacting the compound containing the masked amine with a reducing agent (e.g., LiAlH₄). When amine is masked as an imide (e.g., phthalimide), the amine can be unmasked by reacting with an amine unmasking agent known in the art, e.g., hydrazine.

Hydroxyl Protecting Groups and Hydroxyl Protecting Group Removing Agents

Hydroxyl protecting groups can be as defined herein. In particular, a hydroxyl protecting group can be an acyl, a sulfonyl, an arylalkyl (e.g., benzyl or p-methoxybenzyl), an aryl (e.g., p-methoxyphenyl), or an optionally substituted silyl (e.g., TMS, TES, TBS, TIPS, TBDPS, or TPS). Hydroxyl protecting groups, hydroxyl protecting agents, and hydroxyl protecting reaction conditions can be selected to protect selectively certain hydroxyl groups in a compound, while leaving other hydroxyl groups unprotected. The choice of hydroxyl protecting groups for a compound can facilitate subsequent deprotection strategies, as some hydroxyl protecting groups can be removed in the presence of others using appropriate hydroxyl protecting group removing agents. Some of these strategies involving the choice of silyl hydroxyl protecting groups are discussed in, e.g., Silicon-Based Blocking Agents, Gelest, Inc., 2011.

Hydroxyl protecting group removing agents are those agents that can react with a compound having a protected hydroxyl group to afford the compound with a deprotected hydroxyl group. Hydroxyl protecting group removing agents and deprotection reaction conditions can be those known in the art. In a non-limiting example, hydroxyl masked as silyl ether can be unmasked by a reaction with a fluoride source (e.g., a fluoride salt, such as KF or TBAF). Alternatively, hydroxyl protected as TMS or TES ether can be deprotected by a reaction with a Brønsted acid (e.g., a carboxylic acid). In another non-limiting example, hydroxyl protected as an ester can be deprotected by a reaction with a C₁₋₆ alkoxide (e.g., alkali C₁₋₆ alkoxide or alkali earth C₁₋₆ alkoxide). In yet another non-limiting example, hydroxyl protected as an arylalkyl ether (e.g., 1-arylalk-1-yl ether) can be deprotected using a reduction reaction, e.g., with Pd/C and H₂ or with Na/NH₃. Alternatively, hydroxyl protected as an alkoxy-arylalkyl ether (e.g., MPM ether) can be deprotected by a reaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In still another non-limiting example, hydroxyl protected as alkoxyalkyl ether (e.g., 1-alkoxyalk-1-yl) or THP ether can be deprotected by a reaction with a Brønsted acid. Cyclic protected diols, such as acetals or ketals (e.g., as 2-alkyl-1,3-dioxolane, 2,2-dialkyl-1,3-dioxolane, 2-alkyl-1,3-dioxane, or 2,2-dialkyl-1,3-dioxane), can be deprotected by a reaction with a Brønsted acid (e.g., a carboxylic acid).

Dihydroxylation and Oxidative Carbon-Carbon Bond Cleavage Dihydroxylation reaction produces diols from olefins. The reaction conditions can be those known in the art. Dihydroxylation reaction may be direct (e.g., Sharpless dihydroxylation, Upjohn dihydroxylation, or Milas dihydroxylation) or indirect (e.g., through epoxidation/hydrolysis, diborylation/oxidation, or carboxylation/hydrolysis (e.g., Woodward reaction or Prévost reaction)). A direct dihydroxylation reaction can be performed using an osmium complex (e.g., OsO₄ or osmate salt). A catalytic quantity of the osmium complex can be used in the dihydroxylation reactions in combination with an additional oxidizing agent (e.g., N-methylmorpholine N-oxide or hydrogen peroxide). The dihydroxylation reaction can be rendered stereoselective by including a chiral ligand (e.g., in AD-mix, which is a mixture of osmate and a chiral ligand).

When a dihydroxylation reaction is performed with an osmium complex and a periodate salt as oxidizing agent, the carbon-carbon double bond of an olefin can be cleaved to afford two carbonyl groups. The transformation of an olefin to two carbonyl groups is referred to herein as a cleavage reaction. Cleavage reaction conditions can be those known in the art. Non-limiting examples of cleavage reaction conditions can be ozonolysis reaction conditions or a reaction with an osmium complex (e.g., OsO₄ or osmate salt) and a periodate salt. A vicinal diol can be cleaved by sodium periodate or potassium permanganate.

Epimerizations

Epimerization reactions can be used to invert a stereogenic center having an undesired stereochemical identity. For example, through epimerization, R stereogenic center can be converted to S stereogenic center and vice versa. Epimerization of a stereogenic sp³-carbon bonded to one hydrogen atom and to one hydroxyl group can be achieved through a reaction sequence involving oxidation of the hydroxyl group to a carbonyl group followed by a 1,2-reduction reaction. The 1,2-reduction reaction can provide the desired stereochemical identity diastereoselectively, or the reaction can be carried out using a chiral catalyst, chiral auxiliary, or a chiral reducing agent. Non-limiting examples of chiral reducing agents include alpine borane and prapine borane. Non-limiting examples of 1,2-reduction reactions involving chiral catalysts are Corey-Bakshi-Shibata reduction, Noyori hydrogenation, and Noyori transfer hydrogenation, The oxidation/reduction reaction sequence can be carried out in situ using dynamic kinetic resolution. A dynamic kinetic resolution can further involve a reaction with a hydroxyl protecting agent, which removes the desired stereoisomer from the reduction/oxidation equilibrium. In a non-limiting example, a dynamic kinetic resolution of chiral secondary alcohols can involve reduction/oxidation equilibration using η⁵-Ph₅CpRu(CO)₂H in combination with enantioselective esterification using isopropenyl acetate catalyzed by a lipase enzyme (e.g., lipase B from Candida Antarctica, see, e.g., Martin-Matute et al., J. Am. Chem. Soc., 127:8817-8825, 2005).

Epimerization can also be carried out on a compound containing a tetrahydropyran-2-yl-acetaldehyde moiety, in which carbon 2 of the pyran ring exhibits an undesired stereochemical identity. Contacting this compound with L-proline can provide equilibrium between two stereoisomers. If other, non-equilibrating stereogenic centers are present in the compound, the most stable stereoisomer will be present in a larger quantity relative to other stereoisomer(s) in equilibrium with the most stable stereoisomer.

The following examples are meant to illustrate the invention. They are not meant to limit the invention in any way.

EXAMPLES Example 1 Preparation of the C.1-C.15 Fragment

(2S,3S,4R,5R)-2-allyl-4-(benzyloxy)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)tetrahydrofuran-3-ol

A 3:1 diasteremeric mixture (600 g) of (R)-3-((2R,3R,4S,5S)-5-allyl-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldibenzoate and (S)-3-((2R,3R,4S,5S)-5-allyl-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldibenzoate was dissolved in methanol (1800 mL) at ambient temperature. Potassium carbonate (241 g, 1742 mmol) was added, and the resulting mixture was stirred between 55 and 60° C. for 4 h. Water (1500 mL) was added, and the resulting mixture was extracted four times with n-heptane (2400 mL each time). The aqueous layer was diluted with water (1200 mL) and extracted twice with ethyl acetate (3000 mL each time). The combined organic layers were concentrated in vacuo and azeotroped twice with toluene (1200 mL, each time). Upon addition of the acetone (1200 mL), white insoluble materials were generated. The mixture was filtered through 200 g of silica gel pad, which was then rinsed with acetone (1200 mL). The combined filtrate was concentrated in vacuo to give 216 g of brown oil, which was dissolved in acetone (864 mL) at ambient temperature. 2,2-Dimethoxypropane (103 mL, 841 mmol) and sulfuric acid (1.9 mL, 35 mmol) were added. The resulting mixture was stirred for 4 h and then treated with saturated aqueous NaHCO₃ (8%) (216 mL) and water (540 mL). The resulting mixture was extracted twice with MTBE (864 mL each time). The combined organic layers were washed twice with 30% aqueous NaCl (430 mL each time) and then three times with water (450 mL each time). The resulting organic layer was concentrated in vacuo and azeotroped twice with toluene (864 mL) to give 219 g of the target product as a brown oil. ¹H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.31 (s, 3H (minor)) 1.36 (s, 3H (major)) 1.40 (s, 3H) 1.93 (t, J=6.4 Hz, 2H) 1.96-2.09 (m, 1H) 2.32-2.41 (m, 1H) 2.42-2.52 (m, 1H) 3.53-3.62 (m, 1H) 3.66 (td, J=6.7, 4.7 Hz, 1H) 3.79 (dd, J=4.7, 2.1 Hz, 1H (major)) 3.81 (dd, J=4.7, 2.1 Hz, 1H (minor)) 3.97-4.04 (m, 1H) 4.06-4.12 (m, 1H) 4.12-4.17 (m, 1H) 4.24 (dt, J=13.1, 6.5 Hz, 1H) 4.51 (d, J=12.0 Hz, 1H (minor)) 4.54 (d, J=12.0 Hz, 1H (major)) 4.65 (d, J=11.7 Hz, 1H (major)) 4.66 (d, J=12.0 Hz, 1H (minor)) 5.05-5.18 (m, 2H) 5.77-5.93 (m, 1H) 7.28-7.41 (m, 5H).

4-(((2R,3S,4S,5S)-5-allyl-3-(benzyloxy)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane

A 3:1 diastereomeric mixture of (2S,3S,4R,5R)-2-allyl-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)tetrahydrofuran-3-ol and (2S,3S,4R,5R)-2-allyl-4-(benzyloxy)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)tetrahydrofuran-3-ol (219 g, 629 mmol) was azeotroped with anhydrous THF (329 mL). The resulting oil was added into a reactor with DMF (329 mL). TBAI (46.4 g, 126 mmol) was added, and the resulting mixture was cooled to a temperature ranging from 0 to 5° C. 1.0 M tert-Butyl alcohol, potassium derivative (691 mL, 691 mmol) was added at such rate to maintain the internal temperature below 10° C. Upon addition, the reaction was allowed to stir for 15 minutes. alpha-Chloro-4-methoxytoluene (98 mL, 720 mmol) was then added at such rate to maintain internal temperature below 15° C. Upon addition, the reaction was stirred between 0-5° C. After complete consumption of the starting material, the reaction was quenched with MeONa (25%) in MeOH solution (21.6 mL, 94.3 mmol) diluted in anhydrous methanol (288 mL) at such a rate that internal temperature remained below 10° C. The mixture was then allowed to warm to 20-25° C. and then concentrated in vacuo to remove volatiles. The remaining solution was partitioned between water (1095 mL) and MTBE (1643 mL). The organic layer was washed twice with 30% aqueous NaCl (876 mL), dried over MgSO₄, filtered and concentrated in vacuo. The resulting residue was diluted with MTBE (219 mL), and remaining solid was filtered off. The filtrate was concentrated in vacuo to give 295 g of the target product as a reddish brown oil. ¹H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.31 (s, 3H (minor)) 1.35 (s, 3H (major)) 1.37-1.42 (m, 3H) 1.87-2.03 (m, 2H) 2.26-2.52 (m, 2H) 3.57 (t, J=7.9 Hz, 1H) 3.72 (dd, J=7.3, 3.5 Hz, 1H (major)) 3.74 (d, J=3.2 Hz, 1H (minor)) 3.78-3.86 (m, 5H) 3.98-4.14 (m, 2H) 4.15-4.30 (m, 1H) 4.33-4.41 (m, 2H) 4.42-4.46 (m, 1H) 4.57 (d, J=12.0 Hz, 1H) 5.00-5.10 (m, 2H) 5.73-5.91 (m, 1H) 6.85-6.91 (m, 2H) 7.19-7.24 (m, 2H) 7.27-7.39 (m, 5H)

2-((2S,3S,4S,5R)-4-(benzyloxy)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)acetaldehyde

3:1 diastereomeric mixture of 2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)acetaldehyde and 2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)acetaldehyde (100 g, 213 mmol) was dissolved in 1,4-dioxane (600 mL) and water (200 mL). 2,6-Lutidine (49.7 mL, 427 mmol) and a solution of osmic acid (2.5 wt %, 25 mL, 2.458 mmol) in t-BuOH were added. The resulting mixture was cooled to a temperature below 20° C. and sodium metaperiodate (137 g, 640 mmol) was added. After being stirred for 5 h at ambient temperature, the reaction mixture was treated with water (1250 mL). The resulting mixture was extracted twice with toluene (1000 mL each time). The combined organic layers were washed sequentially with a solution of sodium sulfite (40.3 g, 320 mmol) in water (200 mL), 1.0 M hydrochloric acid in water (500 mL, 500 mmol), saturated aqueous NaHCO₃ (8%) (200 mL), and 30% aqueous NaCl (200 mL). The organic layer was concentrated in vacuo, and the residue was filtered through a silica-gel pad (150 mL), which was rinsed with n-heptane/ethyl acetate (1/1=1000 mL). Concentration in vacuo provided 102 g of the target product as dark brown oil. ¹H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.31 (s, 1H (minor)) 1.35 (s, 3H (major)) 1.39 (s, 3H) 1.87-2.14 (m, 2H) 2.66 (dd, J=5.8, 1.8 Hz, 1H) 2.70-2.78 (m, 1H) 3.55 (dd, J=8.2, 7.3 Hz, 1H) 3.76 (dd, J=2.9, 0.8 Hz, 1H (major)) 3.77 (dd, J=2.7, 0.6 Hz, 1H (minor)) 3.79-3.84 (m, 4H) 4.00 (dd, J=7.8, 6.0 Hz, 1H (major)) 4.06 (dd, J=8.2, 5.8 Hz, 1H (minor)) 4.12 (dt, J=8.9, 3.8 Hz, 1H) 4.17-4.24 (m, 1H) 4.28 (ddd, J=7.3, 5.6, 2.9 Hz, 1H) 4.36-4.50 (m, 3H) 4.54 (d, J=12.2 Hz, 1H) 4.55 (d, J=11.9 Hz, 1H) 6.85-6.91 (m, 2H) 7.15-7.39 (m, 7H) 9.73 (t, J=2.0 Hz, 1H)

2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)-1-(furan-2-yl)ethan-1-ol

Furan (22.40 mL, 308.0 mmol) and THF (800 mL) were added into a reactor and cooled down to 0° C. n-BuLi (1.6 M, 110 mL, 276 mmol) was added while keeping the internal temperature below 15° C. After being stirred for 1 h at a temperature between 10 and 20° C., the resulting solution was cooled to a temperature below −20° C. A solution of a 3:1 diastereomeric mixture of 2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)acetaldehyde and 2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)acetaldehyde (102 g, 212 mmol) in THF (300 mL) was added while keeping the internal temperature below −10° C. The resulting reaction mixture was stirred at a temperature between −5 and −15° C. for 1 h. Saturated aqueous NH₄Cl (27 wt %) (500 mL) and water (200 mL) were added, and the mixture was allowed to warm to ambient temperature. The layers were separated, and the organic layer was washed twice with 30% aqueous NaCl (400 mL) and concentrated in vacuo. The residue was filtered through a silica gel pad (300 mL), rinsing with n-heptane/ethyl acetate (3/2, 1300 mL). Concentration of the filtrate afforded 94 g of the target product as a brown oil.

4-(((2R,3S,4S,5S)-3-(benzyloxy)-5-((E)-2-(furan-2-yl)vinyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane

2-((2S,3S,4S,5R)-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)-1-(furan-2-yl)ethan-1-ol (94 g) was dissolved in dimethylacetamide (893 mL). Methyltriphenoxyphosphonium iodide (99 g, 218 mmol) was added while keeping the internal temperature below 25° C. The resulting reaction was kept stirring between 20-25° C. in dark for 2.5 h. The reaction mixture was diluted with MTBE (1410 mL) and cooled down below 10° C. A solution of KOH (88 g, 1571 mmol) in water (1128 mL) was added while keeping the internal temperature below 30° C. The aqueous layer was separated out and extracted twice with MTBE (940 mL). The combined organic layers were washed three times with 30% aqueous NaCl (1128 mL) and concentrated in vacuo. The residue was filtered through a silica gel pad (200 mL), which was then rinsed with n-heptane/ethyl acetate (2/1, 1500 mL). Concentration of the filtrate gave 87.9 g of the target product as brown oil. ¹H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.31 (s, 3H (minor)) 1.35 (s, 3H (major)) 1.40 (s, 3H) 1.87-2.20 (m, 2H) 3.58 (t, J=7.3 Hz, 1H) 3.78-3.81 (m, 3H) 3.88 (d, J=3.4 Hz, 1H (major)) 3.89 (d, J=3.7 Hz, 1H (minor)) 4.03 (dd, J=7.8, 6.0 Hz, 1H (minor)) 4.09 (dd, J=8.2, 6.1 Hz, 1H (major)) 4.17 (dt, J=9.5, 3.7 Hz, 1H) 4.22-4.31 (m, 1H) 4.36 (dd, J=7.3, 3.4 Hz, 1H) 4.42-4.51 (m, 3H) 4.59 (d, J=12.5 Hz, 1H (major)) 4.60 (d, J=11.9 Hz, 1H (minor)) 6.15-6.26 (m, 2H) 6.37 (dd, J=3.2, 2.0 Hz, 1H) 6.39-6.49 (m, 1H) 6.84-6.89 (m, 2H) 7.19-7.24 (m, 2H) 7.26-7.38 (m, 5H)

(2R)-1-((2S,3R,4S,5R)-4-(benzyloxy)-5-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)-2-(furan-2-yl)ethane-1,2-diol

To a reactor were added (DHQ)₂PHAL (1.267 g, 1.627 mmol), potassium osmium(VI) oxide (0.216 g, 0.651 mmol), potassium carbonate (67.5 g, 488 mmol), and potassium ferricyanide(III) hydrate (161 g, 488 mmol). Water (847 mL) and 2-methylpropan-2-ol (424 mL) were added. The resulting mixture was cooled below 7° C. Methane sulfonamide (18.57 g, 195 mmol) followed by a solution of a 3:1 diastereomeric mixture of (R)-4-(((2R,3S,4S,5S)-3-(benzyloxy)-5-((E)-2-(furan-2-yl)vinyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane and (S)-4-(((2R,3S,4S,5S)-3-(benzyloxy)-5-((E)-2-(furan-2-yl)vinyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)methyl)-2,2-dimethyl-1,3-dioxolane (84.7 g, 162.693 mmol) in tert-butanol (424 mL) was added. The resulting mixture was stirred for 3 days between 13-18° C. Sodium sulfite (103 g, 813 mmol) and water (339 mL) were added, and the resulting mixture was stirred for 30-60 min while warming to ambient temperature. The mixture was extracted twice with ethyl acetate (2100 mL). The combined organic layers were washed with 2M aqueous KOH (296 mL) and 30% aqueous NaCl (424 mL). Concentration in vacuo followed by silica gel plug purification using a 25-66% gradient of ethyl acetate in n-heptane as eluent provided 71.6 g of the target product as a brown oil. ¹H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.33-1.38 (m, 3H) 1.39-1.42 (m, 3H) 1.85-2.09 (m, 2H) 3.57 (t, J=7.8 Hz, 1H) 3.78 (d, J=3.1 Hz, 1H) 3.81 (s, 3H) 3.83-3.87 (m, 1H) 3.89 (br. s., 1H) 4.04-4.12 (m, 3H) 4.16-4.24 (m, 1H) 4.34-4.49 (m, 3H) 4.62 (d, J=11.6 Hz, 1H (major)) 4.63 (d, J=11.6 Hz, 1H (minor)) 4.73 (d, J=7.0 Hz, 1H (major)) 4.76 (d, J=6.1 Hz, 1H (minor)) 6.34-6.37 (m, 2H) 6.86-6.91 (m, 2H) 7.16-7.24 (m, 2H) 7.27-7.44 (m, 6H).

3-((2R,3S,4R,5S)-3-(benzyloxy)-5-((2R)-2-(furan-2-yl)-1,2-dihydroxyethyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diol

3:1 diastereomeric mixture of (2R)-1-((2S,3R,4S,5R)-4-(benzyloxy)-5-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)-2-(furan-2-yl)ethane-1,2-diol and (2R)-1-((2S,3R,4S,5R)-4-(benzyloxy)-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)-2-(furan-2-yl)ethane-1,2-diol (71.6 g, 129 mmol) was dissolved in acetic acid (501 mL). Water (125 mL) was added, and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo and azeotroped with toluene (500 mL). The residue was filtered through silica-gel pad (200 mL), which was then rinsed with n-heptane/ethyl acetate (1/1, 1 L) and ethyl acetate (3.5 L). Concentration of the filtrate gave 69.4 g of the target product as brown oil.

3-((2R,3S,4R,5R)-5-((1S)-acetoxy((2R)-6-acetoxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diyl diacetate

A 3:1 diastereomeric mixture of (R)-3-((2R,3S,4R,5S)-3-(benzyloxy)-5-((1R,2R)-2-(furan-2-yl)-1,2-dihydroxyethyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diol and (S)-3-((2R,3S,4R,5S)-3-(benzyloxy)-5-((1R,2R)-2-(furan-2-yl)-1,2-dihydroxyethyl)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diol (69.4 g) was dissolved in THF (989 mL) and water (247 mL) and cooled down below 5° C. Sodium bicarbonate (21.53 g, 256.3 mmol) and sodium acetate (10.51 g, 128.1 mmol) were added. NBS (23.94 g, 134.5 mmol) was added while keeping the internal temperature below 5° C. After being stirred for 1 h at a temperature between 0 and 5° C., the reaction mixture was treated with a solution of potassium iodide (10.63 g, 64.06 mmol) in water (165 mL) and diluted with EtOAc (2000 mL). The organic layer was washed with a solution of sodium thiosulfate (16.21 g, 102.5 mmol) in water (198 mL) followed by 30% aqueous NaCl (132 mL). Solvents were removed in vacuo. The resulting residue (71 g) was dissolved in dichloromethane (613 mL) and cooled down to 0° C. Pyridine (198 mL, 2444 mol), acetic anhydride (121 mL, 1285 mol) and 4-dimethylaminopyridine (1.57 g, 12.8 mmol) were added. After being stirred overnight at a temperature between 0 and 15° C., the reaction mixture was treated with saturated aqueous NH₄Cl (27 wt %) (545 mL) and water (136 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (341 mL). The combined organic layers were washed twice with 0.5 M aqueous hydrochloric acid (409 mL) followed by 30% aqueous NaCl (477 mL). Concentration followed by filtration through a silica gel pad (60 mL), which was then rinsed with heptane/ethyl acetate (1/1, 1500 mL), provided 92 g of the target product as a brown oil.

3-((2R,3S,4R,5R)-5-((1S)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diyl diacetate

3-((2R,3S,4R,5R)-5-((1S)-Acetoxy((2R)-6-acetoxy-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diyldiacetate (92 g, 129 mmol) was dissolved in acetonitrile (902 mL) and cooled to −15° C. Allyltrimethylsilane (51.3 mL, 323 mmol) followed by BF₃.OEt₂ (21.26 mL, 167.7 mmol) was added while keeping internal temperature below −10° C. The resulting solution was stirred at a temperature between −10 and 0° C. until the reaction was complete. Saturated aqueous NaHCO₃ (8%) (902 mL) and MTBE (721 mL) were then added, and the resulting mixture was allowed to warm to ambient temperature. The layers were separated, and the aqueous layer was extracted with MTBE (721 mL). The combined organic layers were washed twice with 30% aqueous NaCl (721 mL) and concentrated in vacuo. The residue was diluted with MTBE (1500 mL) and washed sequentially with 1M HCl (250 mL), saturated aqueous NaHCO₃ (8%) (250 mL), and 30% aqueous NaCl (250 mL). Concentration followed by filtration through a silica gel pad (100 mL), which was then rinsed with n-heptane/ethyl acetate (2/3, 1200 mL), provided 54.2 g of the target product as a brown oil.

3-((2R,3R,4R,5R)-5-((1S)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyl diacetate

3-((2R,3S,4R,5R)-5-((1S)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-((4-methoxybenzyl)oxy)tetrahydrofuran-2-yl)propane-1,2-diyldiacetate (54.2 g) was dissolved in dichloromethane (542 mL) and treated with water (136 mL) and DDQ (25.3 g, 111 mmol). After being stirred for 2 h at ambient temperature, the reaction mixture was diluted with dichloromethane (700 mL) and water (700 mL). Saturated aqueous NaHCO₃ (8%) (870 mL) and sodium thiosulfate (35.2 g, 223 mmol) were added, and the resulting mixture was stirred at ambient temperature for 10 min. The layers were separated, and the aqueous layer was extracted with dichloromethane (271 mL). The combined organic layers were washed with saturated aqueous NaHCO₃ (8%) (325 mL) and 30% aqueous NaCl (217 mL). Concentration in vacuo and purification by silica gel column chromatography using a 20-60% gradient of ethyl acetate in n-heptane as eluent afforded 31.2 g of the target product as a brown oil. 1H NMR (a 9:3:3:1 mixture of 4 diastereomers, 400 MHz, CDCl₃) δ ppm 1.84-1.98 (m, 2H) 2.04 (d, J=12.9 Hz, 9H) 2.43 (d, J=8.2 Hz, 2H) 3.89 (dt, J=7.6, 2.1 Hz, 1H) 3.98-4.06 (m, 2H) 4.07-4.18 (m, 2H) 4.34 (dd, J=11.9, 3.3 Hz, 1H) 4.43 (d, J=5.1 Hz, 1H) 4.55 (d, J=11.7 Hz, 1H) 4.60-4.65 (m, 1H) 4.66-4.73 (m, 1H) 5.12-5.23 (m, 3H) 5.51 (dd, J=6.6, 5.1 Hz, 1H (major)) 5.55 (dd, J=5.9, 4.7 Hz, 1H (minor)) 5.75-5.88 (m, 1H) 6.12 (dd, J=10.6, 2.3 Hz, 1H) 6.90 (dd, J=10.4, 1.4 Hz, 1H (minor)) 6.95 (dd, J=10.6, 2.3 Hz, 1H (major)) 7.27-7.40 (m, 5H)

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-oxotetrahydrofuran-2-yl)propane-1,2-diyl diacetate

To 3-((2R,3R,4R,5R)-5-((1S)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldiacetate (27.4 g, 48.9 mmol) was added dichloromethane (219 mL) at ambient temperature. Sodium bicarbonate (12.32 g, 146.6 mmol), Dess-Martin periodinane (30.1 g, 70.872 mmol) and water (0.176 mL, 9.78 mmol) were added. The resulting mixture was stirred at ambient temperature until all starting material was consumed. It was then diluted with water (301 mL) and MTBE (301 mL). Sodium bicarbonate (12.32 g, 146.6 mmol) and sodium thiosulfate (19.32 g, 122.2 mmol) were added, and the resulting mixture was stirred at ambient temperature over 10 min. The layers were separated, and the aqueous layer was extracted with MTBE (219 mL). The combined organic layers were washed with saturated aqueous NaHCO₃ (8%) (137 mL) and 30% aqueous NaCl (137 mL). Concentration in vacuo followed by azeotroping with toluene provided 33.1 g of the target product as a dark brown oil.

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyl diacetate

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-oxotetrahydrofuran-2-yl)propane-1,2-diyl diacetate was dissolved in dichloromethane (406 mL) and MeOH (406 mL) and cooled to a temperature below −75° C. Sodium borohydride (2.75 g, 72.3 mmol) was added portionwise while keeping the internal temperature below −75° C. After 1 h, acetone (95 mL, 1290 mmol) was added while keeping the internal temperature below −75° C. Saturated aqueous NH₄Cl (27 wt %) (216 mL), water (108 mL) and MTBE (325 mL) were added. The resulting mixture was allowed to warm up to ambient temperature. The layers were separated and the aqueous layer was extracted with MTBE (271 mL). The combined organic layers were washed twice with 30% aqueous NaCl (189 mL) and dried over MgSO₄. Filtration followed by concentration in vacuo provided 30.8 g of brown thick oil, which was dissolved in dichloromethane (271 mL). To the resulting solution was added manganese dioxide (42.1 g, 484 mmol). The resulting slurry was vigorously stirred at ambient temperature overnight. 40 g of Celite® was then added, and the resulting slurry was stirred at ambient temperature for 20 min. Filtration through a Celite® pad, concentration in vacuo, and purification by silica gel column chromatography using n-heptane/ethyl acetate (1/2) as eluent gave 23.8 g of the target product as a foam solid.

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxotetrahydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyl diacetate

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxo-3,6-dihydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-hydroxytetrahydrofuran-2-yl)propane-1,2-diyldiacetate (20 g, 35.7 mmol) was dissolved in deoxygenated toluene (460 mL) at ambient temperature. The resulting solution was purged with nitrogen for 1 h and deoxygenated (purged with nitrogen for 40 min) water (1.22 mL, 67.8 mmol) was added. Hydrido(triphenylphosphine)copper(I) hexamer (16.0 g, 8.16 mmol) was added in 3 portions. The resulting red slurry was stirred over 4 h. Upon completion, the reaction was exposed to air. Copper-containing decomposition products precipitated out. The resulting brown slurry was filtered through a Celite pad, which was then rinsed with toluene until no product was observed in eluent. Concentration in vacuo followed by purification by column chromatography using a 20-66% gradient of ethyl acetate in n-heptane as eluent gave 18.07 g of the target product as a brown oil.

3-((2R,3S,3aS,8aR,9S,9aR)-9-acetoxy-7-allyl-3-(benzyloxy)-4a-methoxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyl diacetate

3-((2R,3S,5S)-5-((1R)-acetoxy((2R)-6-allyl-3-oxotetrahydro-2H-pyran-2-yl)methyl)-3-(benzyloxy)-4-oxotetrahydrofuran-2-yl)propane-1,2-diyldiacetate (23.4 g, 41.6 mmol) was dissolved in methanol (281 mL). ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid (1.1 g, 5.0 mmol) was added, and the resulting solution was stirred at 60° C. until all starting material was consumed. The mixture was cooled to ambient temperature and treated with TEA (0.870 mL, 6.24 mmol). Solvents were removed, and the residue was dissolved in ethyl acetate (468 mL). The resulting solution was washed with 30% aqueous NaCl (70.2 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane (140 mL) and pyridine (46.8 mL) at ambient temperature. Acetic anhydride (23.59 mL, 249.6 mmol) and 4-dimethylaminopyridine (0.508 g, 4.16 mmol) were added, and the resulting solution was stirred at ambient temperature for 1 h. The reaction mixture was treated with saturated aqueous NH₄Cl (27 wt %) (140 mL), water (46.8 mL) and MTBE (281 mL). The organic layer was separated and washed sequentially with 1M aqueous hydrochloric acid (94 mL), saturated aqueous NaHCO₃ (8%) (70.2 mL), and 30% aqueous NaCl (70.2 mL). Drying over MgSO₄, filtration, concentration and purification by silica gel column chromatography using a 25-40% gradient of ethyl acetate in n-heptane as eluent provided 12.3 g of the target product as a pale brown oil.

¹H NMR (9:3:3:1 mixture of 4 diastereomers, CDCl₃) δ ppm 1.29-1.48 (m, 1H) 1.54-1.78 (m, 3H) 1.93-2.16 (m, 11H) 2.17-2.40 (m, 2H) 3.25 (s, 3H (minor 1)) 3.29 (s, 3H (minor 2)) 3.30 (s, 3H (major)) 3.55 (d, J=11.1 Hz, 1H (major)) 3.56 (d, J=11.4 Hz, 1H (minor)) 3.62-3.75 (m, 1H) 3.98-4.26 (m, 4H) 4.29-4.38 (m, 1H) 4.39-4.45 (m, 1H) 4.50 (d, J=11.7 Hz, 1H (minor 2)) 4.52 (d, J=12.0 Hz, 1H (major)) 4.57 (d, J=12.0 Hz, 1H (minor 3)) 4.59 (d, J=12.3 Hz, 1H (minor 1)) 4.73-4.83 (m, 1H) 4.96-5.09 (m, 2H) 5.18-5.27 (m, 1H) 5.26 (dd, J=11.3, 6.0 Hz, 1H) 5.37 (dd, J=11.4, 5.9 Hz, 1H (major)) 5.72 (dd, J=17.1, 10.1 Hz, 1H (minor)) 7.27-7.40 (m, 5H)

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-(benzyloxy)-7-(2-hydroxyethyl)-4a-methoxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyl diacetate

3-((2R,3S,3aS,8aR,9S,9aR)-9-acetoxy-7-allyl-3-(benzyloxy)-4a-methoxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate (13.5 g, 23.4 mmol) was dissolved in 1,4-dioxane (176 mL) and water (58.1 mL). 2,6-Lutidine (8.18 mL, 70.2 mmol), 4.0% osmic acid in water (3.27 mL, 0.515 mmol), and sodium metaperiodate (25.04 g, 117.1 mmol) were added. The resulting solution was stirred at ambient temperature until all starting material was consumed. Upon completion, water (203 mL) and toluene (203 mL) were added. The aqueous layer was separated and extracted with toluene (135 mL). The combined organic layers were washed sequentially with 1M hydrochloric acid (67.5 mL, 67.5 mmol), saturated aqueous NaHCO₃ (8%) (54.0 mL), 10% aqueous Na₂S₂O₃ (40.5 mL), and 30% aqueous NaCl (81 mL). The resulting solution was dried over MgSO₄ and concentrated in vacuo. The residue (15.6 g) was dissolved in methanol (201 mL) at ambient temperature. The resulting solution was cooled to a temperature below 10° C., and L-proline (0.801 g, 6.96 mmol) was added in one portion. The resulting solution was stirred overnight while warming to ambient temperature. After being stirred for additional 6 h at ambient temperature, the reaction mixture was diluted with MTBE (335 mL), and saturated aqueous NaHCO₃ (8%) (201 mL) and water (108 mL) were added. The layers were separated, and the aqueous layer was extracted twice with MTBE (201 mL each time). The combined organic layers were washed twice with 30% aqueous NaCl (107 mL), dried over MgSO₄, and concentrated in vacuo. The residue (21 g) was dissolved in methanol (201 mL) and cooled to 0° C. Sodium borohydride (1.14 g, 30.1 mmol) was added in 5 portions. Once the reaction was complete, saturated aqueous NH₄Cl (27 wt %) (134 mL) and water (67.1 mL, 3723.506 mmol) were added. The mixture was extracted twice with ethyl acetate (470 mL). The combined organic layer was washed with 30% aqueous NaCl (107 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was filtered through a silica gel pad (200 mL), which was then rinsed with n-heptane/ethyl acetate (1/1, 400 mL) and ethyl acetate (1200 mL). The combined filtrate was concentrated in vacuo to give 10.75 g of the target product.

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-(benzyloxy)-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyl diacetate

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-(benzyloxy)-7-(2-hydroxyethyl)-4a-methoxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate (10.6 g, 18.3 mmol) was dissolved in dichloromethane (106 mL) at 17-22° C. Pyridine (10.60 mL, 131 mmol), pivaloyl chloride (6.74 mL, 54.8 mmol), and 4-dimethylaminopyridine (0.446 g, 3.65 mmol) were added. After 2 h at ambient temperature, saturated aqueous NaHCO₃ (8%) (106 mL), water (31.8 mL), and MTBE (159 mL) were added. After 10 min of being stirred at ambient temperature, the layers were separated, and the organic layer was washed with saturated aqueous NaHCO₃ (8%) (53.0 mL) and 30% aqueous NaCl (53.0 mL). Drying over MgSO₄, concentration in vacuo, and purification by silica-gel column chromatography using a 33-50% gradient of ethyl acetate in n-heptane as eluent provided 12.1 g of the target product as a pale brown oil.

¹H NMR (major isomer only, 400 MHz, CDCl₃) δ ppm 1.14-1.20 (m, 9H) 1.43-1.88 (m, 6H) 1.93-2.14 (m, 1H) 2.02 (s, 3H) 2.03 (s, 3H) 2.05 (s, 3H) 2.16-2.28 (m, 1H) 3.26 (s, 3H) 3.32-3.42 (m, 1H) 3.76 (s, 1H) 4.01-4.20 (m, 6H) 4.24 (t, J=4.0 Hz, 1H) 4.36 (dd, J=12.0, 2.9 Hz, 1H) 4.58 (d, J=12.3 Hz, 1H) 4.80 (dd, J=12.0, 3.8 Hz, 1H) 5.02 (s, 1H) 5.13-5.29 (m, 2H) 7.30-7.39 (m, 5H)

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-hydroxy-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyl diacetate

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-(benzyloxy)-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate (12.08 g, 18.17 mmol) was dissolved in methanol (121 mL) and EtOAc (60.4 mL). 10% Palladium on carbon (4.8 g) was added, and the resulting mixture was treated with hydrogen using a hydrogen balloon at ambient temperature until all starting material was consumed. The resulting mixture was purged with nitrogen and filtered through a Celite® pad (20 g), which was then rinsed with EtOAc until no target product remained in the pad. The filtrate was concentrated in vacuo and azeotroped with toluene (72.5 mL). The residue was filtered through a silica-gel pad (200 mL), which was then rinsed with n-heptane/ethyl acetate (50% to 100%). Concentration of the combined filtrate provided 9.5 g of the target product.

3-((2R,3S,3aR,7R,8aR,9S,9aR)-9-acetoxy-3-((diisopropylsilyl)oxy)-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyl diacetate

3-((2R,3S,3aS,7R,8aR,9S,9aR)-9-acetoxy-3-hydroxy-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate (9.5 g, 16.5 mmol) was dissolved in dichloromethane (95 mL, 1480 mmol) at ambient temperature. Imidazole (3.49 g, 51.3 mmol), diisopropylchlorosilane (5.64 mL, 33.1 mmol), and 4-dimethylaminopyridine (0.202 g, 1.65 mmol) were added. After being stirred for 2 h at ambient temperature, the reaction was quenched with saturated aqueous NH₄Cl (27 wt %) (95 mL). The resulting mixture was extracted with MTBE (143 mL), and the organic layer was washed with 30% aqueous NaCl (47.5 mL) and dried over MgSO₄. Filtration, concentration in vacuo, and purification by silica gel column chromatography using 180 g silica gel pretreated with n-heptane/EtOAc/TEA (500/50/1 mL) provided 9.5 g of the target product as a colorless oil. ¹H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) d ppm 0.99-1.10 (m, 14H) 1.18 (s, 9H) 1.44-2.00 (m, 7H) 2.01-2.07 (m, 9H) 2.08-2.19 (m, 1H) 3.26 (s, 3H) 3.33-3.43 (m, 1H) 3.72 (t, J=3.2 Hz, 1H (minor)) 3.76 (t, J=3.8 Hz, 1H (major)) 3.98-4.19 (m, 5H) 4.28 (s, 1H) 4.35 (dd, J=12.2, 2.8 Hz, 1H) 4.47 (dd, J=6.9, 4.5 Hz, 1H) 4.96 (t, J=2.9 Hz, 1H (minor)) 5.01 (t, J=3.4 Hz, 1H (major)) 5.12-5.32 (m, 1H)

3-((2R,3S,3aR,7R,8aS,9R,9aR)-9-acetoxy-3-((fluorodiisopropylsilyl)oxy)-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyl diacetate

3-((2R,3S,3aR,7R,8aR,9S,9aR)-9-acetoxy-3-((diisopropylsilyl)oxy)-4a-methoxy-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate (9.50 g, 13.8 mmol) was dissolved in dichloromethane (143 mL, 2215 mmol) and cooled below −25° C. BF₃.OEt₂ (2.55 mL, 20.7 mmol) was added, and the resulting pale yellow solution was stirred for 5 h while warming to −10° C. Saturated aqueous NaHCO₃ (8%) (95 mL) and dichloromethane (47.5 mL) were added. The layers were separated, and the aqueous layer was extracted with dichloromethane (28.5 mL). The combined organic layers were washed with 30% aqueous NaCl (47.5 mL) and dried over MgSO₄. Concentration in vacuo and purification by silica gel column chromatography using a 20-100% gradient of ethyl acetate in n-heptane as eluent provided 5.24 g of the target product.

¹H NMR (4:1 diastereomeric mixture, 400 MHz, CDCl₃) d ppm 1.12-1.16 (m, 14H) 1.18 (s, 9H) 1.23-1.47 (m, 2H) 1.64-1.77 (m, 3H) 1.78-1.88 (m, 1H) 1.91-2.03 (m, 2H) 2.04 (s, 3H) 2.05 (s, 3H) 2.09 (s, 3H) 2.92 (dd, J=10.3, 9.4 Hz, 1H) 3.29-3.40 (m, 1H) 3.84-3.97 (m, 2H) 3.98-4.19 (m, 4H) 4.29 (dd, J=12.0, 3.2 Hz, 1H) 4.38-4.49 (m, 2H) 5.13-5.25 (m, 1H) 5.32 (dd, J=10.5, 7.9 Hz, 1H).

2-((2R,3S,3aR,4aS,7R,8aR,9R,9aS)-2-(2,3-dihydroxypropyl)-3-((diisopropyl(methoxy)silyl)oxy)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate

3-((2R,3S,3aR,4aS,7R,8aS,9R,9aR)-9-acetoxy-3-((fluorodiisopropylsilyl)oxy)-7-(2-(pivaloyloxy)ethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)propane-1,2-diyldiacetate (297 mg, 0.439 mmol) was dissolved in methanol (4.46 mL) at ambient temperature. 0.5 M Magnesium methoxide in MeOH (1.573 mL, 0.878 mmol) was added and the resulting solution was stirred overnight. Additional the magnesium methoxide solution (0.5 M, 1.57 mL, 0.878 mmol) was added, and the resulting solution was stirred at ambient temperature for 10 h before quenching by saturated aqueous NH₄Cl (27 wt %) (5.0 mL). EtOAc (10 mL) and water (2.0 mL) were added, and the resulting white mixture was stirred at ambient temperature for 20 min. The layers were separated, and the aqueous layer was extracted twice with EtOAc (16 mL). The combined organic layers were washed twice with 30% aqueous NaCl (4.0 mL) and dried over MgSO₄. Filtration and concentration in vacuo provided 0.211 g of the target product as an off-white foam solid.

2-((2R,3S,3aR,4aS,7R,8aR,9R,9aS)-3-((diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate

2-((2R,3S,3aR,4aS,7R,8aR,9R,9aS)-2-(2,3-dihydroxypropyl)-3-((diisopropyl(methoxy)silyl)oxy)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (0.190 g, 0.338 mmol) was dissolved in acetone (2.280 mL). 2,2-Dimethoxypropane (0.570 mL, 4.641 mmol) and pyridinium p-toluenesulfonate (0.017 g, 0.068 mmol) were added. The resulting solution was stirred at ambient temperature over 1 h and treated with saturated aqueous NaHCO₃ (8%) (3.80 mL). The resulting mixture was extracted twice with MTBE (10 mL), and the combined organic layers were washed with 30% aqueous NaCl (1.900 mL, 33.299 mmol) and dried over MgSO₄. Filtration and concentration gave 0.214 g of the target product.

2-((2R,3S,3aR,4aS,7R,8aS,9aR)-3-((diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-oxodecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate

2-((2R,3S,3aR,4aS,7R,8aR,9R,9aS)-3-((Diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (0.214 g) was dissolved in dichloromethane (4.07 mL). Sodium bicarbonate (0.113 g, 1.349 mmol) and Dess-Martin periodinane (0.286 g, 0.674 mmol) were added. After being stirred at ambient temperature overnight, the reaction mixture was diluted with MTBE (10.17 mL, 85.34 mmol) and water (4.07 mL, 225.7 mmol). A saturated aqueous NaHCO₃ (8%) (2.033 mL) and sodium thiosulfate (0.213 g, 1.349 mmol) were then added, and the resulting mixture was stirred at ambient temperature for 30 min. The layers were separated, and the aqueous layer was extracted with MTBE (6.10 mL). The combined organic layers were washed with 30% aqueous NaCl (2.033 mL) and dried over MgSO₄. Filtration followed by concentration gave 206 mg of the target product.

2-((2R,3S,3aR,4aS,7R,8aR,9S,9aS)-3-((diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate

2-((2R,3S,3aR,4aS,7R,8aS,9aR)-3-((diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-oxodecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (206 mg) was dissolved in methanol (4.04 mL) and cooled to 0° C. Sodium borohydride (0.019 g, 0.504 mmol) was then added.

The reaction was stirred for 30 min at 0° C. and quenched with saturated aqueous NH₄Cl (27 wt %) (4.0 mL). The resulting mixture was extracted twice with MTBE (8.0 mL). The combined organic layers were washed with 30% aqueous NaCl (2.0 mL) and dried over MgSO₄. Filtration followed by concentration in vacuo provided 216 mg of the target product.

2-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3,9-dihydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate

2-((2R,3S,3aR,4aS,7R,8aR,9S,9aS)-3-((diisopropyl(methoxy)silyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-9-hydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (216 mg) was dissolved in THF (4.0 mL) at ambient temperature and cooled below 10° C. 1.0 M TBAF in THF (0.500 mL, 0.50 mmol) was added. Once all starting material was consumed, saturated aqueous NH₄Cl (27 wt %) (4.0 mL) was added, and the resulting mixture was extracted twice with MTBE (10.04 mL). The combined organic layers were washed with 30% aqueous NaCl (2.0 mL) and dried over MgSO₄. Filtration followed by concentration and purification by silica gel column chromatography using a 33-80% gradient of ethyl acetate in n-heptane as eluent gave 117 mg of the target product as a white solid.

¹H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.19 (s, 9H) 1.35 (s, 3H (minor)) 1.36 (s, 3H (major)) 1.40 (s., 3H (minor)) 1.41 (s, 3H (major)) 1.70-2.01 (m, 7H) 2.13-2.21 (m, 1H) 3.00 (dd, J=9.7, 2.1 Hz, 1H (major)) 3.01 (dd, J=9.7, 2.1 Hz, 1H (minor)) 3.46-3.54 (m, 1H) 3.59 (dd, J=8.2, 7.3 Hz, 1H (major)) 3.61 (dd, J=8.1, 7.2 Hz, 1H (minor)) 4.00-4.22 (m, 8H) 4.22-4.31 (m, 1H) 4.43 (dd, J=8.9, 4.5 Hz, 1H)

A co-crystal of the desired product and the C3-epimer was obtained, and the structure was confirmed by single crystal X-ray analysis (see FIG. 7).

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2,3-dihydroxypropyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate

2-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3,9-dihydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (110 mg, 0.24 mmol) was dissolved in DMF (2.200 mL) at ambient temperature. Imidazole (131 mg, 1.92 mmol), tert-butyldiphenylchlorosilane (308 μl, 1.20 mmol), and 4-dimethylaminopyridine (14.65 mg, 0.12 mmol) were added. The resulting mixture was stirred at 45° C. overnight. Additional imidazole (163 mg, 2.40 mmol), TBDPS-Cl (308 μl, 1.199 mmol), and 4-dimethylaminopyridine (29.3 mg, 0.24 mmol) were added. After being stirred at a temperature between 60 and 70° C. for 10 h, the reaction mixture was treated with MTBE (15 mL) and a saturated NH₄Cl solution (8 mL). The aqueous layer was separated and extracted with MTBE (10 mL). The combined organic layers were washed twice with 30% aqueous NaCl (3 mL each) and dried over MgSO₄. Filtration followed by purification by silica gel column chromatography provided 0.75 g of 2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate of 10 wt % purity along with mono silyl ether (81 mg) and the starting material (19 mg). The mono silyl ether (81 mg, 0.116 mmol) and the recovered starting material (19 mg, 0.041 mmol) were dissolved in dichloromethane (1.5 mL) and cooled to 0° C. 2,6-Lutidine (0.068 mL, 0.581 mmol) and tert-butyldiphenylsilyl trifluoromethanesulfonate (0.097 mL, 0.314 mmol) were added. After being stirred overnight at ambient temperature, the reaction mixture was treated with saturated NH₄Cl solution (5 mL). The resulting mixture was extracted twice with MTBE (12 mL). The combined organic layers were washed with 1M aqueous hydrochloric acid (3 mL), saturated NaHCO₃ (2 mL) and 30% aqueous NaCl (2 mL). Drying over MgSO₄ and concentration in vacuo provided 0.215 g of thick oil, which was combined into the previously isolated product. To the combined crude product were added acetic acid (8.0 mL) and water (2.0 mL) at ambient temperature. The resulting mixture was stirred at 25-30° C. overnight. Additional acetic acid (5 mL) and water (1 mL) were added, and the reaction mixture was stirred at a temperature between 35 and 40° C. for 4 h. Concentration in vacuo followed by purification by silica gel column chromatography using a 20-60% gradient of ethyl acetate in n-heptane as eluent provided 0.171 g of the target product as a film oil.

¹H NMR (3:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 1.05-1.12 (m, 18H) 1.18 (s, 9H) 1.28-1.68 (m, 5H) 1.82-1.93 (m, 2H) 1.95-2.10 (m, 1H) 2.63 (d, J=4.7 Hz, 1H (major)) 2.75 (d, J=5.6 Hz, 1H (minor)) 3.00 (dd, J=9.7, 4.1 Hz, 1H (major)) 3.15 (dd, J=10.3, 4.7 Hz, 1H (minor)) 3.23-3.30 (m, 1H) 3.31-3.38 (m, 1H) 3.43-3.51 (m, 1H) 3.61 (dd, J=6.7, 4.7 Hz, 1H) 3.70 (t, J=5.0 Hz, 1H) 3.79-3.84 (m, 1H) 3.87 (ddd, J=9.3, 6.2, 3.2 Hz, 1H) 3.95 (t, J=6.6 Hz, 2H) 4.06-4.14 (m, 1H) 4.23 (t, J=5.3 Hz, 1H) 4.30 (dd, J=6.3, 5.1 Hz, 1H (major)) 4.33 (dd, J=6.6, 4.2 Hz, 1H (minor)) 7.28-7.45 (m, 12H) 7.62-7.79 (m, 8H)

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-oxoethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate

To 2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2,3-dihydroxypropyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (143 mg, 0.16 mmol) were added THF (2.9 mL) and water (1.4 mL) at ambient temperature. The resulting mixture was cooled to 0° C. and treated with sodium periodate (180 mg, 0.842 mmol). After being stirred at ambient temperature for 2 h, the reaction mixture was diluted with MTBE (12 mL). The mixture was washed with saturated aqueous NaHCO₃ (8%) (3.0 mL) and 30% aqueous NaCl (2.0 mL) and dried over MgSO₄. Filtration followed by concentration in vacuo provided 136 mg of the target product.

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxybut-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-oxoethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (136 mg) was dissolved in THF (2.72 mL, 33.2 mmol) and cooled to −30° C. Vinyl magnesium bromide (1.0 M in THF, 0.394 mL, 0.394 mmol) was added and the resulting solution was stirred at a temperature between −30 and −35° C. for 20 min. Saturated aqueous NH₄Cl (27 wt %) (4.0 mL) was added, and the resulting mixture was warmed to ambient temperature. The mixture was extracted with MTBE (10 mL), and the organic layer was washed with 30% aqueous NaCl (2.0 mL) and dried over MgSO₄. Filtration and concentration of the filtrate provided 129 mg of the target product as a white foam solid.

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxybut-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (129 mg) was dissolved in dichloromethane (3.0 mL) at ambient temperature. Imidazole (39.4 mg, 0.579 mmol), chlorotriethylsilane (0.049 mL, 0.289 mmol), and 4-dimethylaminopyridine (0.884 mg, 7.24 μmol) were added. After being stirred at ambient temperature for 2 h, the reaction was quenched with saturated aqueous NH₄Cl (27 wt %, 5.0 mL). The resulting mixture was extracted with MTBE (15 mL). The organic layer was washed with 30% aqueous NaCl (3.0 mL), dried over MgSO₄, filtered, and concentrated in vacuo to give 0.155 g of the desired product as an oil.

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethanol

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (155 mg, 0.145 mmol) was dissolved in dichloromethane (2.91 mL) and cooled to −78° C. DIBAL in toluene (1.0 M, 0.724 mL, 0.724 mmol) was added, and the resulting solution was stirred for 1 h. Methanol (0.1 mL, 2.5 mmol) and a solution of Rochelle's salt (613 mg, 2.173 mmol) in water (2.9 mL) were added, and the resulting mixture was allowed to warm to ambient temperature. The layers were separated, and the aqueous layer was extracted with dichloromethane (2.91 mL). The combined organic layers were washed with 30% aqueous NaCl (1.457 mL) and dried over MgSO₄. Filtration, concentration and purification by silica gel column chromatography using a 20-33% gradient of ethyl acetate in n-heptane as eluent provided 107 mg of the target product as a white foam. ¹H NMR (1:1 diatereomeric mixture, 400 MHz, CDCl₃) δ ppm 0.48-0.57 (m, 3H) 0.58-0.67 (m, 3H) 0.83-0.93 (m, 4.5H) 0.94-1.02 (m, 4.5H) 1.06-1.18 (m, 18H) 1.28-1.72 (m, 6.5H) 1.85-1.94 (m, 1H) 1.95-2.04 (m, 0.5H) 2.12 (dd, J=10.3, 4.4 Hz, 1H) 2.98 (dd, J=9.7, 3.2 Hz, 0.5H) 3.11 (dd, J=9.7, 6.2 Hz, 0.5H) 3.30 (t, J=5.1 Hz, 0.5H) 3.33-3.40 (m, 0.5H) 3.41-3.57 (m, 2.5H) 3.58-3.70 (m, 2H) 3.84-3.90 (m, 0.5H) 3.92-4.02 (m, 0.5H) 4.03-4.25 (m, 2.5H) 4.32 (dd, J=5.9, 3.2 Hz, 0.5H) 4.34-4.41 (m, 0.5H) 4.93-5.16 (m, 2H) 5.59-5.80 (m, 1H) 7.24-7.46 (m, 12H) 7.57-7.83 (m, 8H).

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetaldehyde

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethanol (80 mg, 0.087 mmol) was dissolved in dichloromethane (1.60 mL, 24.9 mmol) at ambient temperature. Sodium bicarbonate (36.5 mg, 0.434 mmol) and Dess-Martin periodinane (110 mg, 0.26 mmol) were added. After being stirred for 3 h, the reaction mixture was treated with MTBE (10 mL), saturated aqueous NaHCO₃ (8%) (2.0 mL), water (1.0 mL), and sodium thiosulfate (137 mg, 0.868 mmol). The resulting mixture was stirred at ambient temperature over 30 min. The layers were separated, and the organic layer was washed with 30% aqueous NaCl (2.0 mL) and dried over MgSO₄. Filtration, concentration, and filtration through silica gel plug with n-Heptane/EtOAc (2/1, 20 mL) provided 76 mg of the target product as a colorless film.

¹H NMR (1:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 0.45-0.56 (m, 3H) 0.56-0.65 (m, 3H) 0.79-1.00 (m, 9H) 1.06-1.17 (m, 18H) 1.27-1.40 (m, 4.5H) 1.59-1.67 (m, 1H) 1.77 (m, 0.5H) 1.85-1.99 (m, 1H) 2.04-2.09 (m, 1H) 2.14 (br. s., 0.5H) 2.16-2.20 (m, 0.5H) 2.23 (dd, J=4.5, 1.9 Hz, 0.5 H) 2.30 (dd, J=7.9, 2.1 Hz, 0.5H) 2.97 (dd, J=9.7, 3.2 Hz, 0.5H) 3.03 (m, J=9.8, 5.7 Hz, 0.5H) 3.47 (dd, J=6.3, 4.5 Hz, 0.5H) 3.54-3.76 (m, 2.5H) 3.92 (dd, J=7.0, 5.6 Hz, 0.5H) 3.98-4.29 (m, 3.5H) 4.37 (dd, J=6.2, 3.2 Hz, 1H) 4.94 (dt, J=10.3, 1.4 Hz, 0.5H) 4.99-5.07 (m, 1H) 5.09-5.18 (m, 0.5H) 5.58-5.78 (m, 1H) 7.27-7.44 (m, 12H) 7.63-7.82 (m, 8H) 9.43 (t, J=2.1 Hz, 0.5H) 9.51 (t, J=1.9 Hz, 0.5H)

Example 2 Preparation of the Substrate for C.15-C.16 Macrocyclization (E)-3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)acrylaldehyde

To a stirred solution of 3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propan-1-ol (2.5 g, 2.9 mmol) in DMSO/Toluene (20/40 mL) was added IBX (4.11 g, 14.7 mmol), benzoic acid (1.79 g, 14.7 mmol), and sodium bicarbonate (0.42 g, 5.0 mmol) at ambient temperature. After degassing, the reaction mixture was stirred for 6 h at 75° C. (reaction flask was wrapped with aluminum-foil to protect from light). Additional IBX (2 g after 5 h, 3 g after 10 h) was added, and the mixture was stirred for additional 6 h at 77° C. 150 mL MTBE was added, and the resulting mixture was washed twice with saturated NaHCO₃ solution. The organic layer was dried over MgSO₄, filtered, and purified by silica gel column chromatography to give 1.5 g of the target product. ¹H NMR (400 MHz, CDCl₃) δ ppm −0.03-0.02 (m, 12H) 0.79-0.82 (m, 18H) 1.01 (d, J=6.6 Hz, 3H) 1.38-1.341 (m, 1H) 1.42-1.54 (m, 3H) 1.58-1.85 (m, 4H) 1.90-1.95 (m, 1H) 1.97-2.16 (m, 3H) 2.35-2.45 (m, 2H) 2.46-2.49 (m, 2H) 2.76-2.81 (m, 1H) 2.91-3.00 (m, 2H) 3.34 (s, 3H) 3.35-3.42 (m, 2H) 3.46-3.62 (m, 2H) 3.56-3.62 (m, 1H) 3.65-3.68 (m, 2H) 3.70-3.77 (m, 2H) 4.07-4.28 (m, 1H) 4.66-4.70 (m, 2H) 4.78 (br s, 1H) 4.84-4.90 (m, 1H) 6.17 (ddd, J=15.6, 7.8, 1.6 Hz, 1H) 6.70 (dd, J=15.6, 4.6 Hz, 1H) 7.50-7.55 (m, 2H) 7.60-7.64 (m, 1H) 7.87 (d, J=9.9 Hz, 2H) 9.49 (d, J=7.8 Hz, 1H)

(E)-3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)prop-2-en-1-ol

(E)-3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)acrylaldehyde (3.4 g) was dissolved in THF (70 mL) and cooled to −70° C. DIBAL in toluene (1.0 M, 5.42 mL) was added at this temperature, and the resulting solution was slowly warmed to −50° C. over a period of 2 h. At this time, the reaction was quenched with methanol, followed by the addition of aqueous ammonium chloride and MTBE. The resulting mixture was stirred for 2 h at room temperature. Extractive workup of this mixture furnished a crude product, which was purified by flash silica gel chromatography with hexanes/ethyl acetate (3:1 to 1:1) as eluent to afford 2.4 g of the desired product as an oil. ¹H NMR (400 MHz, CDCl₃) δ ppm −0.03-0.05 (m, 12H) 0.80-0.86 (m, 18H) 0.94-1.03 (m, 4H) 1.31-1.41 (m, 2H) 1.42-1.53 (m, 3H) 1.61-1.88 (m, 3H) 1.92-1.98 (m, 2H) 2.10-2.17 (m, 2H) 2.20-2.33 (m, 1H) 2.46-2.49 (m, 1H) 2.50-2.66 (m, 1H) 2.92-3.01 (m, 2H) 3.38 (s, 3H) 3.39-3.43 (m, 2H) 3.47-3.59 (m, 1H) 3.61-3.63 (m, 1H) 3.64-3.78 (m, 3H) 4.07-4.08 (m, 1H) 4.02-4.05 (m, 1H) 4.36-4.41 (m, 1H) 4.60-4.63 (br s, 1H) 4.71 (br s, 1H) 4.85-4.89 (m, 1H) 5.62-5.68 (m, 1H) 5.79-5.81 (m, 1H) 7.52-7.56 (m, 2H) 7.60-7.64 (m, 1H) 7.87-7.89 (m, 1H).

(S)-5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane

To a solution of (E)-3-((2R,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)prop-2-en-1-ol (0.42 g, 0.50 mmol) in dry THF (5 mL) at 5° C. was added sodium hydride (60% in oil, 30 mg, 0.74 mmol)), and the resulting slurry was aged at ambient temperature for 20 min. Allyl bromide (0.060 mL, 0.69 mmol) and TBAI (0.018 mg, 0.049 mmol) were added. The resulting mixture was stirred for 16 h at ambient temperature. The reaction was quenched by addition of saturated aqueous NH₄Cl. Extraction with ethyl acetate, concentration in vacuo, and purification by silica gel column chromatography gave 0.28 g of the target product as an oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.037 (s, 3H) 0.044 (s, 3H) 0.09 (s, 3H) 0.10 (s, 3H) 0.87-0.89 (m, 18H) 1.06 (d, J=6.6 Hz, 3H) 1.22-1.32 (m, 1H) 1.37-1.48 (m, 2H) 1.52-1.62 (m, 2H) 1.71-1.78 (m, 1H) 1.79-1.93 (m, 2H) 1.96-2.07 (m, 1H) 2.13-2.26 (m, 2H) 2.31-2.42 (m, 1H) 2.52-2.60 (m, 1H) 2.63-2.74 (m, 1H) 2.96-3.08 (m, 2H) 3.35-3.41 (m, 1H) 3.43 (s, 3H) 3.48 (m, J=5.5 Hz, 1H) 3.54-3.62 (m, 2H) 3.64-3.71 (m, 1H) 3.76-3.87 (m, 3H) 3.94-4.00 (m, 4H) 4.26-4.34 (m, 1H) 4.43 (q, J=6.6 Hz, 1H) 4.63-4.72 (m, 1H) 4.77 (d, J=1.6 Hz, 1H) 4.85 (s, 1H) 4.89-4.96 (m, 1H) 5.17 (dq, J=10.5, 1.3 Hz, 1H) 5.27 (dq, J=17.2, 1.6 Hz, 1H) 5.65-5.82 (m, 2H) 5.84-5.98 (m, 1H) 7.61 (d, J=7.8 Hz, 2H) 7.65-7.73 (m, 1H) 7.90-8.01 (m, 2H).

(1S)-1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-1-(phenylsulfonyl)propan-2-ol

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetaldehyde (76 mg, 0.083 mmol) was dissolved in THF (0.760 mL, 9.275 mmol) and cooled to 0° C. n-Butyl lithium (1.6 M, 0.108 mL, 0.174 mmol) was added, and the resulting solution was stirred at 0° C. for 30 min and then cooled to −78° C. A solution of (S)-5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (147 mg, 0.165 mmol) in n-hexane (1.52 mL) was added, and the reaction mixture was stirred at −78° C. for 1 h. Saturated aqueous NH₄Cl (27 wt %) (3.0 mL), water (1.0 mL), and MTBE (8.0 mL) were added, and the resulting mixture was warmed up to ambient temperature. The organic layer was separated, washed with 30% aqueous NaCl (2.0 mL), and dried over MgSO₄. Filtration, concentration in vacuo, and purification by silica gel column chromatography using a 20-50% gradient of ethyl acetate in n-heptane as eluent provided 152 mg of the target product.

(1S)-1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-1-(phenylsulfonyl)propan-2-one

(1S)-1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-1-(phenylsulfonyl)propan-2-ol (152 mg, 0.084 mmol) was dissolved in dichloromethane (3.04 mL) at ambient temperature. Sodium bicarbonate (35.3 mg, 0.42 mmol) and Dess-Martin periodinane (89 mg, 0.21 mmol) were added, and the resulting mixture was stirred at ambient temperature overnight. MTBE (7.600 mL), water (1.52 mL), saturated aqueous NaHCO₃ (8%) (3.04 mL), and sodium thiosulfate (133 mg, 0.84 mmol) were added. After stirring at ambient temperature for 1 h, the layers were separated. The organic layer was washed with 30% aqueous NaCl (3.0 mL) and dried over MgSO₄. Filtration, concentration, and purification by silica gel column chromatography using a 12-25% gradient of ethyl acetate in n-heptane as eluent provided 77 mg of the target product.

1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one

(1S)-1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-1-(phenylsulfonyl)propan-2-one (77 mg) was dissolved in THF (1.2 mL) and MeOH (0.77 mL). The resulting solution was cooled to −78° C. and treated with 0.1 M samarium diiodide (1.28 mL, 0.128 mmol) for 1 h. The reaction was quenched with a mixture of Rochelle's salt (385 mg, 1.36 mmol), potassium carbonate (385 mg, 2.79 mmol), and water (3.85 mL). MTBE (5.0 mL) was added, and the resulting mixture was warmed to ambient temperature. The layers were separated, and the aqueous layer was extracted with MTBE (5.0 mL). The combined organic layers were washed with 30% aqueous NaCl (2.0 mL) and dried over MgSO₄. Filtration, concentration, and purification by silica gel column chromatography using a 25-33% gradient of ethyl acetate in n-heptane as eluent provided 46 mg of the target product. ¹H NMR (1:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm −0.01-0.13 (m, 12H) 0.46-0.65 (m, 6H) 0.84-0.99 (m, 27H) 1.02-1.16 (m, 21H) 1.22-1.36 (m, 1H) 1.45-1.82 (m, 10H) 1.87-2.29 (m, 9H) 2.32-2.45 (m, 2H) 2.65-2.77 (m, 1H) 2.98 (dd, J=9.5, 3.1 Hz, 0.5H) 3.04 (dd, J=9.7, 5.3 Hz, 0.5H) 3.20 (t, J=4.0 Hz, 1H) 3.30 (s, 1.5H) 3.34 (m, 1.5H) 3.39-3.90 (m, 12H) 3.92-4.03 (m, 4H) 4.06-4.24 (m, 3H) 4.31-4.39 (m, 1H) 4.39-4.51 (m, 2H) 4.73-4.86 (m, 3H) 4.91-5.06 (m, 3H) 5.16 (d, J=1.2 Hz, 1H) 5.22-5.30 (m, 1H) 5.58-5.82 (m, 3H) 5.84-5.97 (m, 1H) 7.26-7.43 (m, 12H) 7.62-7.80 (m, 8H)

Example 3 Preparation of a Compound of Formula (ID) Through C.15-C.16 Macrocyclization

1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one (32 mg, 0.019 mmol) was dissolved in toluene (7.0 mL). Hoveyda-Grubbs 2^(nd) generation catalyst (1.448 mg, 2.304 μmol) was added, and the resulting solution was heated to 70° C. After being stirred at 70° C. overnight, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. Silica gel column chromatography of the residue using a 10-50% gradient of ethyl acetate in n-heptane as eluent afforded 9.3 mg of the target product. MS m/z 1591.1 [M+Na]⁺. ¹H NMR (1.5:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 0.01-0.10 (m, 12H) 0.58 (td, J=7.8, 5.7 Hz, 6H) 0.81-0.97 (m, 30H) 1.00-1.12 (m, 18H) 1.17-2.80 (m, 24H) 2.88 (t, J=9.1 Hz, 1H (major)) 2.97 (t, J=9.4 Hz, 1H (minor)) 3.29-3.35 (m, 1H) 3.37 (s, 3H (major)) 3.42 (s, 3H (minor)) 3.42-3.85 (m, 10H), 3.96-4.15 (m, 3H) 4.34 (m, 2H) 4.40-4.48 (m, 1H) 4.54-4.70 (m, 1H) 4.78-4.82 (m, 1H) 4.85 (br. s., 1H) 4.90-4.92 (m, 1H) 4.96-5.01 (m, 1H) 5.51 (dd, J=15.2, 7.0 Hz, 1H (minor)) 5.81 (ddd, J=15.4, 7.6, 1.3 Hz, 1H (major)) 6.32 (dd, J=15.2, 3.5 Hz, 1H (major)) 6.59 (dd, J=15.4, 8.9 Hz, 1H (minor)) 7.28-7.45 (m, 12H) 7.52-7.78 (m, 8H)

Compound 1 (4.6 mg, 2.9 μmol) was dissolved in THF (1.1 mL) at ambient temperature. To the solution was added acetic acid (0.5 mL) and water (0.3 mL). After being stirred for 3 h at ambient temperature, the resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using a 10-33% gradient of ethyl acetate in n-heptane as eluent to give 4.0 mg of compound 2. ¹H NMR (major isomer, 400 MHz, CDCl₃) δ ppm −0.02-0.09 (m, 12H) 0.88 (s, 9H) 0.89 (s, 9H) 1.03 (s, 9H) 1.05 (d, J=6.4 Hz, 3H) 1.07 (s, 9H) 1.25-2.81 (m, 24H) 2.95 (t, J=9.1 Hz, 1H) 3.33 (d, J=3.5 Hz, 1H) 3.40 (s, 3H) 3.44-3.53 (m, 2H) 3.53-3.61 (m, 2H) 3.66-3.85 (m, 8H) 4.08 (dd, J=8.6, 3.7 Hz, 1H) 4.29-4.40 (m, 2H) 4.42-4.48 (m, 1H) 4.60-4.69 (m, 2H) 4.79 (s, 1H) 4.86 (br. s., 1H) 4.90 (s, 1H) 4.99 (br. s., 1H) 5.79 (ddd, J=15.7, 7.9, 1.6 Hz, 1H) 6.54 (dd, J=15.4, 3.7 Hz, 1H) 7.28-7.45 (m, 12H) 7.52-7.76 (m, 8H)

Compound 2 (4.0 mg, 2.751 μmol) was dissolved in dichloromethane (1.0 mL) at ambient temperature. Sodium bicarbonate (1.4 mg, 0.017 mmol) and Dess-Martin periodinane (3.5 mg, 8.3 μmol) were added, and the resulting mixture was stirred at ambient temperature overnight. MTBE (3.0 mL), water (1.0 mL), saturated aqueous NaHCO₃ (8%) (1.0 mL), and sodium thiosulfate (2.174 mg, 0.014 mmol) were added. The resulting mixture was stirred at ambient temperature over 30 min. The organic layer was separated, washed with 30% aqueous NaCl (0.5 mL) and dried over MgSO₄. Filtration followed by concentration in vacuo provided 3.3 mg of compound 3.

Compound 3 (3.3 mg, 2.3 μmol) was dissolved in deoxygenated toluene (0.5 mL) at ambient temperature. Deoxygenated (purged with nitrogen for 40 min) water (2 μL, 0.11 mmol) followed by Stryker's reagent (4.5 mg, 2.3 μmol) was added. After 1 h, additional Stryker's reagent (˜2 mg) was added. After being stirred for additional 1 h, the reaction mixture was treated with air. A precipitate formed. Concentration followed by purification by column chromatography using a 10-20% gradient of ethyl acetate in n-heptane as eluent afforded 2.5 mg of compound 4.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.03-0.10 (m, 12H) 0.88 (s, 9H) 0.90 (s, 9H) 1.00 (s, 9H) 1.05 (d, J=6.4 Hz, 3H) 1.08 (s, 9H) 1.20-2.20 (m, 21H) 2.25-2.35 (m, 1H) 2.46-2.81 (m, 6H) 2.90-2.99 (m, 1H) 3.05 (t, J=11.7 Hz, 1H) 3.09 (t, J=9.1 Hz, 1H) 3.32 (d, J=2.3 Hz, 1H) 3.42 (s, 3H) 3.48 (dd, J=4.5, 3.7 Hz, 1H) 3.51 (dd, J=10.5, 5.0 Hz, 1H) 3.58 (dd, J=10.4, 5.7 Hz, 1H) 3.69-3.92 (m, 7H) 4.05 (dd, J=8.8, 3.2 Hz, 1H) 4.11-4.20 (m, 1H) 4.35 (m, 1H) 4.37-4.44 (m, 1H) 4.78 (s, 1H) 4.86 (d, J=1.5 Hz, 1H) 4.90 (s, 1H) 4.98 (d, J=1.8 Hz, 1H) 7.27-7.46 (m, 12H) 7.58-7.69 (m, 8H)

To compound 4 (2.5 mg, 1.719 μmol) in a vial was added THF (230 μl) and N,N-dimethylacetamide (88 μl) at ambient temperature. A mixture of TBAF (34 μl, 0.034 mmol) and imidazole hydrochloride (1.8 mg, 0.017 mmol) was added, and the resulting mixture was stirred over 20 h at ambient temperature. A mixture of acetonitrile (60 μL) and water (20 μL) was added, and the resulting mixture was stirred at ambient temperature for 2 days. 30% aqueous NaCl (0.13 mL) and toluene (0.7 mL) were added. The layers were separated, and the aqueous layer was extracted twice with a mixture of THF (1.4 mL) and toluene (1.4 mL). The combined organic layer was concentrated under a stream of nitrogen. The residue was dissolved in dichloromethane (0.2 mL) at ambient temperature, and PPTS (0.80 mg, 3.2 μmol) was added. After 1 h and after 4 h, additional PPTS (0.4 mg and 3 mg, respectively) was added. Once all starting material was consumed, the reaction mixture was purified by silica gel column chromatography using heptane/ethyl acetate (1/1), ethyl acetate, and MTBE/MeCN (1/1) as eluent to give 1.6 mg of compound 6. The structure was confirmed by comparison of the ¹H NMR spectrum with the reported spectrum.

¹H NMR (500 MHz, methanol-d₄) δ ppm 1.01-1.10 (m, 2H) 1.14 (d, J=6.6 Hz, 3H) 1.30-1.64 (m, 7H) 1.70-2.54 (m, 17H) 2.67-2.81 (m, 2H) 2.87-2.94 (m, 1H) 2.96-2.98 (m, 1H) 3.38-3.41 (m, 1H) 3.45 (s, 3H) 3.50 (dd, J=11.4, 6.2 Hz, 1H) 3.54 (dd, J=11.0, 4.4 Hz, 1H) 3.69-3.80 (m, 2H) 3.84-3.94 (m, 3H) 4.01 (t, J=10.6 Hz, 1H) 4.10-4.18 (m, 2H) 4.21 (dd, J=6.4, 4.6 Hz, 1H) 4.27-4.39 (m, 2H) 4.51 (d, J=10.6 Hz, 1H) 4.64 (t, J=4.4 Hz, 1H) 4.74 (t, J=4.6 Hz, 1H) 4.86 (br. s., 1H) 4.92 (s, 1H) 5.06 (s, 1H) 5.17 (d, J=1.8 Hz, 1H)

(S)-3-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diol

To a stirred solution of (S)-5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (3.8 g, 4.27 mmol) in THF (50 mL) at 5° C. was added 1M THF solution of TBAF (12.8 mL, 12.8 mmol). The reaction was warmed to room temperature. After aging for 16 h at this temperature, the reaction was quenched by addition of aqueous ammonium chloride (10 mL). After dilution with ethyl acetate (30 mL), the phases were separated. The aqueous layer was back-extracted with ethyl acetate (2×50 mL), and the organic layers were combined. The combined organic layers were dried over MgSO₄. Removal of the solvent under reduced pressure and flash silica gel chromatography of the residue with heptanes-ethyl acetate (2:1 to 1:2) as eluent afforded 2.3 g (81%) of desired product as an oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.34-1.41 (m, 2H) 1.47-1.54 (m, 4H) 1.67-1.77 (m, 3H) 1.86-1.96 (m, 3H) 2.10-2.17 (m, 2H) 2.28-2.33 (m, 1H) 2.51-2.55 (m, 1H) 2.56-2.66 (m, 1H) 2.99-3.08 (m, 2H) 3.29-3.34 (m, 2H) 3.38 (s, 3H) 3.39-3.59 (m, 4H) 3.73-3.78 (m, 1H) 3.84-3.90 (m, 3H) 3.90-3.92 (m, 4H) 4.20-4.28 (m, 1H), 4.37-4.39 (m, 1H) 4.63-4.64 (m, 1H) 4.73 (br s, 1H), 4.78 (br s, 1H) 4.86 (m, 1H) 5.10-5.13 (m, 1H) 5.19-5.23 (m, 1H) 5.66-5.73 (m, 1H) 5.81-5.88 (m, 1H) 7.53-7.57 (m, 2H) 7.62-7.67 (m, 1H) 7.86-7.90 (m, 2H).

(S)-1-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)-3-aminopropan-2-ol

To a stirred solution of (S)-3-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylene-tetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diol (1.05 g, 1.59 mmol) in methylene chloride (30 mL) was added 2,4,6-collidine (0.84 mL, 6.35 mmol) and pyridine (7 μl, 0.08 mmol). The resulting mixture was cooled to −10° C., and Ts₂O (1.1 g, 1.75 mmol) was added in two portions. The reaction was stirred for 3 h at a temperature between −10 and −5° C. and at 0° C. for 2 h. The reaction then was warmed to room temperature, and isopropanol (75 mL) and ammonium hydroxide (85 mL) were added. After aging 16 h at room temperature, additional ammonium hydroxide (20 ml) was added, and stirring was continued for 6 h at a temperature between 26 and 30° C. After removal of organic solvents under reduced pressure, the residue was extracted with methylene chloride (3×40 mL). The combined organic layers were washed with brine and dried over MgSO₄. Removal of the solvent and silica gel chromatography of the residue with hexanes/ethyl acetate (2:1 to pure ethyl acetate) as eluent afforded the desired product as a foam. Since the product was contaminated with small amount of 2,4,6-collidine, it was further purified by precipitation of product from cyclohexane or n-heptane (740 mg, 70.6%). ¹H NMR (400 MHz, CDCl₃) δ ppm 0.95-1.11 (m, 3H) 1.22-1.37 (m, 2H) 1.46-1.50 (m, 2H) 1.78-1.84 (m, 3H) 2.04-2.19 (m, 3H) 2.26-2.37 (m, 2H) 2.50-2.59 (m, 2H) 2.63-2.90 (m, 2H) 2.92-3.04 (m, 2H) 3.12-3.22 (m, 1H) 3.26 (s, 3H) 3.36-3.39 (m, 2H) 3.44-3.49 (m, 1H) 3.54-3.56 (m, 1H) 3.60-3.68 (m, 1H) 3.78-3.94 (m, 4H), 4.03-4.06 (m, 1H) 4.07-4.19 (m, 1H) 4.36-4.38 (m, 1H), 4.58-4.86 (m, 4H) 5.08-5.16 (m, 2H) 5.63-5.68 (m, 2H) 5.66-5.83 (m, 1H) 7.48-7.62 (m, 3H) 7.84-7.89 (m, 2H).

tert-butyl ((S)-3-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)-2-hydroxypropyl)carbamate

To a stirred solution of (S)-1-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylene-tetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)-3-aminopropan-2-ol (0.7 g, 1.06 mmol) and triethylamine (0.22 mL, 1.6 mmol) in methylene chloride (20 mL) was added di-tert-butyl dicarbonate (290 mg, 1.34 mmol) at room temperature. The mixture was aged for 14 h at room temperature under nitrogen with a vent for CO₂ release. After quenching with aq. sat ammonium chloride (15 ml), phases were separated. The aqueous layer was extracted with methylene chloride (15 mL), and the combined organic layers were washed with brine and concentrated to dryness. The resulting crude product was purified by silica gel column chromatography using hexanes-ethyl acetate (3:1 to 1:1) to give the product as an oil (0.6 g, 74%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.15-1.25 (m, 7H) 1.30-1.42 (m, 2H) 1.37 (br s, 9H) 1.43-1.56 (m, 3H) 1.67-1.72 (m, 2H) 1.81-1.93 (m, 2H) 2.09-2.19 (m, 2H) 2.27-2.33 (m, 1H) 2.40-2.50 (m, 1H) 2.51-2.59 (m, 1H) 2.61-2.65 (m, 1H) 3.00-3.10 (m, 2H) 3.20-3.30 (m, 1H) 3.33-3.39 (m, 1H) 3.36 (s, 3H) 3.51-3.53 (m, 1H) 3.65-3.74 (m, 1H) 3.79-3.86 (m, 2H) 3.90-3.91 (m, 3H) 4.24-4.34 (m, 1H) 4.36-4.38 (m, 1H) 4.62 (d, J=1.9 Hz 1H) 4.72 (br s, 1H) 4.77 (br s, 1H) 4.85 (d, J=1.9 Hz, 1H) 4.93 (br s, 1H) 5.12 (dd, J=10.5, 1.5 Hz, 1H), 5.18-5.23 (m, 1H) 5.65-5.72 (m, 2H) 5.80-5.87 (m, 1H) 7.52-7.56 (m, 2H) 7.61-7.65 (m, 1H) 7.845-7.89 (m, 2H).

(S)-tert-butyl 5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

To a stirred solution of tert-butyl ((S)-3-((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylene-tetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)-2-hydroxypropyl)carbamate (0.50 g, 0.66 mmol) in acetone (10 mL) was added 2,2-dimethoxypropane (1.0 mL, 8.16 mmol) and p-toluenesulfonic acid monohydrate (15 mg, 0.08 mmol). The reaction mixture was stirred for 1.5 h at room temperature. After adding sodium bicarbonate (200 mg), the reaction was stirred for additional 10 min.

After dilution with ethyl acetate (40 mL) and saturated aqueous NaHCO₃ (20 mL), the resulting mixture was phase separated. The organic layer was back-extracted with ethyl acetate (25 mL). The combined organic layers were washed with brine and concentrated to dryness. The resulting crude product was further purified by silica gel column chromatography using a gradient from 4:1 to 2:1 of heptanes/ethyl acetate as eluent to give 400 mg of the desired product as an oil (76%). ¹H NMR (400 MHz, CDCl₃) ppm 1.15-1.29 (m, 4H) 1.3-1.5 (m, 4H), 1.40 (br s 9H) 1.49 (s, 6H) 1.66-1.69 (m, 1H) 1.78-1.83 (m, 1H) 1.89-1.98 (m, 1H) 2.03-2.12 (m, 3H) 2.27-2.32 (m, 1H) 2.51-2.59 (m, 1H) 2.61-2.64 (m, 1H) 2.97-3.08 (m, 3H) 3.20-3.33 (m, 1H) 3.37 (s, 3H) 3.46-3.53 (m, 1H) 3.61-3.67 (m, 3H) 3.80-3.91 (m, 4H) 4.07-4.11 (m, 1H) 4.20-4.25 (m, 1H) 4.34-4.37 (m, 1H) 4.65 (d, d=2.0 Hz, 1H) 4.71 (br s, 1H) 4.78 (br s, 1H) 4.84 (d J=2.0 Hz, 1H) 5.10-5.23 (m, 2H) 5.61-5.72 (m, 2H) 5.80-5.87 (m, 1H) 7.53-7.57 (m, 2H) 7.61-7.65 (m, 1H) 7.89-7.90 (m, 2H).

1-((5S)-5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-((1 S)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-hydroxy-1-(phenylsulfonyl)propyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidin-3-yl)-2,2-dimethylpropan-1-one

2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetaldehyde (100 mg, 0.109 mmol) was dissolved in THF (1.0 mL) and cooled to 0° C. n-Butyl lithium (1.6 M, 0.109 mL, 0.174 mmol) was added, and the resulting solution was stirred at 0° C. for 30 min and then cooled to −78° C. A solution of 1-((S)-5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidin-3-yl)-2,2-dimethylpropan-1-one (0.128 g, 0.163 mmol) in n-heptane (2.0 mL), and the reaction mixture was stirred at −78° C. for 1 h. Saturated aqueous NH₄Cl (27 wt %) (4.0 mL), water (1.3 mL), and MTBE (10.5 mL) were added, and the resulting mixture was warmed to ambient temperature. The organic layer was separated, washed with 30% aqueous NaCl (2.6 mL), and dried over MgSO₄. Filtration, concentration in vacuo, and purification by silica gel column chromatography using a 20-66% gradient of ethyl acetate in n-heptane as eluent provided 142 mg of the target product.

(5S)-tert-butyl 5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-((1S)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxo-1-(phenylsulfonyl)propyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

(5S)-tert-butyl 5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-((1S)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-hydroxy-1-(phenylsulfonyl)propyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.142 g, 0.083 mmol) was dissolved in dichloromethane (5.0 mL) at ambient temperature. Sodium bicarbonate (35 mg, 0.41 mmol) and Dess-Martin periodinane (105 mg, 0.248 mmol) were added, and the resulting mixture was stirred at ambient temperature overnight. MTBE (14.2 mL), water (7.1 mL), and sodium thiosulfate (131 mg, 0.83 mmol) were added. After stirring at ambient temperature for 1 h, the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 (8%) (2.84 mL), 30% aqueous NaCl (2.8 mL) and dried over MgSO₄. Filtration, concentration, and filtration through silica gel plug, which was then rinsed with 33% ethyl acetate in n-heptane, provided 120 mg of the target product as a colorless film.

(5S)-tert-butyl 5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate

(5S)-tert-butyl 5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-((1S)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxo-1-(phenylsulfonyl)propyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.120 g, 0.07 mmol) was dissolved in THF (1.9 mL) and MeOH (1.2 mL). The resulting solution was cooled to −78° C. and treated with 0.1 M samarium diiodide (2.1 mL, 0.21 mmol) for 30 min. Additional 0.1 M samarium diiodide (2.1 mL, 0.21 mmol) was added, and the resulting mixture was stirred for 30 min at −78° C. The reaction was quenched with saturated Rochelle's salt solution (8 mL). Water (4 mL) and MTBE (7.2 mL) were added, and the resulting mixture was warmed to ambient temperature. The layers were separated, and the aqueous layer was extracted with MTBE (7.2 mL). The combined organic layers were washed with 30% aqueous NaCl (2.4 mL) and dried over MgSO₄. Filtration, concentration, and purification by silica gel column chromatography using a 20-50% gradient of ethyl acetate in n-heptane as eluent provided 74 mg of the target product as a white foam. ¹H NMR (1:1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 0.45-0.65 (m, 6H) 0.82-1.00 (m, 9H) 1.03 (d, J=7.0 Hz, 1.5H) 1.04 (d, J=7.0 Hz, 1.5H) 1.06-1.17 (m, 18H) 1.27-1.82 (m, 14H) 1.47 (br. s., 12H) 1.85-2.47 (m, 10H) 2.67-2.77 (m, 1H) 2.95-3.07 (m, 1H) 3.08-3.18 (m, 1H) 3.23 (br. s., 1H) 3.29 (s, 1.5H) 3.31 (s, 1.5H) 3.36-3.82 (m, 10H) 3.87 (t, J=6.3 Hz, 0.5H) 3.96 (d, J=5.5 Hz, 4H) 3.99-4.25 (m, 5H) 4.33 (dd, J=6.3, 3.1 Hz, 1H) 4.41 (br. s., 1H) 4.44-4.52 (m, 1H) 4.73-4.82 (m, 2H) 4.83 (s, 1H) 4.91-5.15 (m, 2H) 4.97 (d, J=2.0 Hz, 1H) 5.16 (br. s., 0.5H) 5.18 (s, 0.5H) 5.24 (d, J=1.6 Hz, 0.5H) 5.28 (d, J=1.6 Hz, 0.5H) 5.61-5.81 (m, 3H) 5.84-5.97 (m, 1H) 7.27-7.43 (m, 12H) 7.62-7.81 (m, 8H)

To a solution of Hoveyda-Grubbs 2nd Generation Catalyst (11.8 mg, 0.019 mmol) in toluene (50 mL) at 70° C. was added a solution of (5S)-tert-butyl 5-(((2R,3R,4S,5S)-5-(((2R,4R,6S)-6-(2-((2S,5R)-5-((E)-3-(allyloxy)prop-1-en-1-yl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-((triethylsilyl)oxy)but-3-en-1-yl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-3-methoxytetrahydrofuran-2-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (74 mg, 0.047 mmol) in toluene (10 mL) over 4 h. After stirring at 80° C. for 10 h, the reaction mixture was cooled to ambient temperature and concentrated in vacuo. Silica gel column chromatography of the residue using a 10-33% gradient of ethyl acetate in n-heptane as eluent afforded 35 mg of the target product. ¹H NMR (1.4;1 diastereomeric mixture, 400 MHz, CDCl₃) δ ppm 0.45-0.66 (m, 6H) 0.83-0.96 (m, 9H) 0.99-1.16 (m, 21H) 1.27-3.03 (m, 31H) 1.47 (br. s., 9H) 3.10-3.20 (m, 1H) 3.28-3.91 (m, 12H) 3.35 (s, 3H (major)) 3.40 (s, 3H (minor)) 3.99-4.09 (m, 1H) 4.11-4.17 (m, 1H) 4.29-4.38 (m, 1H) 4.41-4.49 (m, 1H) 4.56-4.70 (m, 1H) 4.77-4.82 (m, 1H) 4.85 (br. s., 1H) 4.89-4.93 (m, 1H) 4.97-5.01 (m, 1H) 5.51 (dd, J=15.4, 7.6 Hz, 1H (minor)) 5.81 (ddd, J=15.4, 7.8, 1.4 Hz, 1H (major)) 6.33 (d, J=15.6 Hz, 1H (major)) 6.58 (dd, J=15.4, 9.2 Hz, 1H (minor)) 7.27-7.45 (m, 12H) 7.58-7.79 (m, 8H)

Compound 7 (35 mg, 24 μmol) was dissolved in THF (3.9 mL) at ambient temperature. To the solution was added acetic acid (1.8 mL) and water (1.1 mL). After being stirred for 3.5 h at ambient temperature, the resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography using a 20-50% gradient of ethyl acetate in n-heptane as eluent to give 32 mg of compound 8.

Compound 8 (32 mg, 23 μmol) was dissolved in dichloromethane (1.9 mL) at ambient temperature. Sodium bicarbonate (11.8 mg, 0.141 mmol) and Dess-Martin periodinane (30 mg, 0.070 mmol) were added, and the resulting mixture was stirred at ambient temperature for 5 h. MTBE (10 mL), water (5 mL), saturated aqueous NaHCO₃ (8%) (2.0 mL), and sodium thiosulfate (56 mg, 0.35 mmol) were added. The resulting mixture was stirred at ambient temperature over 30 min. The organic layer was separated, washed with 30% aqueous NaCl (2 mL) and dried over MgSO₄. Filtration followed by concentration in vacuo and purification by silica gel column chromatography using a 20-50% gradient of ethyl acetate in n-heptane as eluent provided 17 mg of compound 9 as a colorless film. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.98 (s, 9H) 1.04-1.10 (m, 12H) 1.26 (br. s., 3H) 1.29-1.84 (m, 8H) 1.47 (br. s., 9H) 1.55 (s, 3H) 1.90-1.98 (m, 2H) 2.03-2.11 (m, 3H) 2.13-2.24 (m, 2H) 2.46-2.56 (m, 3H) 2.61 (dd, J=16.0, 7.4 Hz, 2H) 2.74-2.83 (dd, J=16.2, 5.7 Hz, 2H) 3.06-3.21 (m, 2H) 3.25-3.33 (m, 1H) 3.37 (d, J=3.9 Hz, 1H) 3.38 (s, 3H) 3.44-3.52 (m, 1H) 3.63-3.93 (m, 8H) 4.06 (dd, J=8.4, 3.7 Hz, 1H) 4.12-4.21 (m, 1H) 4.35 (t, J=6.4 Hz, 1H) 4.46-4.54 (m, 1H) 4.70 (q, J=6.8 Hz, 1H) 4.79 (s, 1H) 4.87-4.95 (m, 2H) 5.03 (d, J=2.0 Hz, 1H) 6.58 (dd, J=16.0, 7.8 Hz, 1H) 6.79 (dd, J=16.0, 5.5 Hz, 1H) 7.28-7.44 (m, 12H) 7.56-7.70 (m, 8H)

Compound 10 (17 mg, 0.012 mmol) was dissolved in deoxygenated toluene (2.6 mL) at ambient temperature. Deoxygenated (purged with nitrogen for 40 min) water (10 μL, 0.57 mmol) followed by Stryker's reagent (24.5 mg, 12 μmol) was added. After 1 h, additional Stryker's reagent (˜20 mg) was added. After being stirred for additional 1 h, the reaction mixture was treated with air. A precipitate formed. Purification by column chromatography using a 10-50% gradient of ethyl acetate in n-heptane as eluent afforded 14.7 mg of compound 11 as a colorless film. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.00 (s, 9H) 1.06 (d, J=6.3 Hz, 3H) 1.08 (s, 9H) 1.23-1.33 (m, 6H) 1.47 (br s, 12H), 1.50-2.00 (m, 11H) 2.06-2.23 (m, 4H) 2.26-2.34 (m, 1H) 2.46-2.54 (m, 1H) 2.54-2.82 (m, 5H) 2.89-3.00 (m, 1H) 3.03-3.12 (m, 2H) 3.13-3.20 (m, 1H) 3.36 (d, J=3.1 Hz, 1H) 3.41 (s, 3H) 3.47-3.51 (m, 1H) 3.63-3.85 (m, 7H) 3.92 (ddd, J=10.9, 7.4, 3.5 Hz, 1H) 4.05 (dd, J=8.8, 3.3 Hz, 1H) 4.11-4.22 (m, 2H) 4.31-4.42 (m, 2H) 4.79 (s, 1H) 4.85 (s, 1H) 4.90 (s, 1H) 4.98 (d, J=1.6 Hz, 1H) 7.26-7.48 (m, 12H) 7.57-7.71 (m, 8H)

To a solution of compound 11 (14.7 mg, 10.8 μmol) in methanol (1 mL) was added p-toluenesulfonic acid monohydrate (2.05 mg, 10.8 μmol) at ambient temperature. The resulting solution was stirred for 3 h and treated with saturated aqueous NaHCO₃ (8%) (3 mL). The resulting mixture was extracted twice with MTBE (12 mL). The combined organic layers were washed with 30% aqueous NaCl (2 ml) and dried over MgSO₄. Filtration followed by concentration in vacuo provided 14.7 mg of compound 13 as colorless oil.

Compound 13 (14.7 mg, 10.7 μmol) was dissolved in THF (1.3 mL) and N,N-dimethylacetamide (0.5 mL) at ambient temperature. 1.0 M TBAF in THF (0.22 mL, 0.022 mmol) and imidazole hydrochloride (11.3 mg, 0.108 mmol) were added, and the resulting mixture was stirred for 20 h at ambient temperature. 30% aqueous NaCl (2 mL) and toluene (3 mL) were added. The layers were separated, and the aqueous layer was extracted twice with a mixture of THF (3 mL) and toluene (3 mL). The combined organic layer was concentrated in vacuo. The residue was dissolved in dichloromethane (1.5 mL) at ambient temperature, and pyridinium p-toluenesulfonate (27 mg, 0.107 mmol) was added. After 3 h, the reaction mixture was purified by silica gel column chromatography using ethyl acetate as eluent to give 6.5 mg of compound 14 as a white foam. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.10 (d, J=6.6 Hz, 3H) 1.28-1.79 (m, 11H) 1.44 (s, 9H) 1.89-2.51 (m, 15H) 2.71 (dd, J=16.0, 10.2 Hz, 1H) 2.85 (dd, J=6.6, 2.0 Hz, 1H) 2.89 (dd, J=7.4, 2.3 Hz, 1H) 3.08-3.17 (m, 1H) 3.26 (d, J=3.1 Hz, 1H) 3.42 (s, 3H) 3.55 (br. s., 1H) 3.58-3.66 (m, 2H) 3.81 (dt, J=9.4, 3.3 Hz, 1H) 3.87-3.99 (m, 3H) 4.03 (dd, J=6.3, 4.3 Hz, 1H) 4.09-4.16 (m, 1H) 4.19 (dd, J=6.4, 4.5 Hz, 1H) 4.29 (dd, J=10.6, 4.3 Hz, 1H) 4.31-4.38 (m, 2H) 4.60 (t, J=4.5 Hz, 1H) 4.69 (t, J=4.7 Hz, 1H) 4.81 (d, J=1.2 Hz, 1H) 4.89 (s, 1H) 4.93 (br. s, 1H) 4.98-5.05 (m, 1H) 5.07 (d, J=2.0 Hz, 1H)

To a solution of compound 14 (3.2 mg, 3.9 μmol) in dichloromethane (0.5 mL) at 0° C. were added 2,6-lutidine (4.9 μL, 0.042 mmol) and trimethylsilyl trifluoromethanesulfonate (5.9 μL, 0.033 mmol) was added, and the resulting solution was warmed to ambient temperature. After 1 h and 3 h, additional 2,6-lutidine (5 μl) and trimethylsilyl trifluoromethanesulfonate (6 μl) were added each time. After additional 1.5 h stirring, the reaction was quenched with water (3 mL). The resulting mixture was extracted twice with dichloromethane (5 mL each time). The combined organic layers were dried over MgSO₄, filtered, and concentrated in vacuo. The residue was dissolved in methanol (0.5 mL), and potassium carbonate (1 mg, 7 μmol) was added at ambient temperature. The resulting mixture was stirred overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography using ethyl acetate, DCM/methanol (9/1), and DCM/methanol/NH₄OH (9/1/0.1) as eluent to give 1.6 mg compound 15. The structure was confirmed by comparison of the ¹H NMR spectrum with the reported spectrum.

¹H NMR (400 MHz, CD₃OD) δ ppm 0.97-1.07 (m, 1H) 1.11 (d, J=6.3 Hz, 3H) 1.30-1.62 (m, 6H) 1.67-2.26 (m, 13H) 2.27-2.42 (m, 3H) 2.42-2.51 (m, 2H) 2.62-2.78 (m, 2H) 2.83-2.96 (m, 3H) 3.04 (dd, J=12.7, 3.3 Hz, 1H) 3.37 (d, J=3.1 Hz, 1H) 3.43 (s, 3H) 3.74 (d, J=11.7 Hz, 1H) 3.82-4.02 (m, 5H) 4.08-4.14 (m, 2H) 4.18 (dd, J=4.7, 6.6 Hz, 1H) 4.26-4.35 (m, 2H) 4.48 (d, J=10.9 Hz, 1H) 4.62 (t, J=4.3 Hz, 1H) 4.71 (t, J=4.3 Hz, 1H) 4.82-4.84 (m, 1H) 4.86-4.87 (m, 1H) 5.02 (br. s, 1H) 5.14 (d, J=1.6 Hz, 1H)

Example 4 Preparation of a Compound of Formula (ID) Through C.3-C.4 Macrocyclization

(R)-1-((3aR,4S,6S,7S,7aR)-7-acetoxy-6-allyltetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1-cyclohexan]-4-yl)ethane-1,2-diyl diacetate

To a solution of (3aR,4S,6S,7R,7aR)-4-((R)-1,2-diacetoxyethyl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexane]-6,7-diyldiacetate (10 g, 21.812 mmol) in acetonitrile (70.0 mL) was added allyltrimethylsilane (10.40 mL, 65.44 mmol). The resulting solution was cooled to 0° C., and BF₃.OEt₂ (5.53 mL, 43.6 mmol) was added, while the internal temperature was maintained below 10° C. After being stirred for 6 h at a temperature between 0 and 10° C., the reaction mixture was treated with saturated aqueous NaHCO₃ (8%) (100 mL). The resulting mixture was extracted with toluene (200 mL). The combined organic layers were washed twice with water (200 mL) and concentrated in vacuo to give 11 g of the target product as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.23-1.85 (m, 10H) 2.07 (s, 3H) 2.10 (s, 3H) 2.14 (s, 3H) 2.21-2.33 (m, 2H) 3.74 (dd, J=7.6, 1.8 Hz, 1H) 4.11 (ddd, J=9.7, 6.6, 5.1 Hz, 1H) 4.25 (dd, J=12.6, 4.4 Hz, 1H) 4.32 (dd, J=7.9, 1.8 Hz, 1H) 4.46 (dd, J=12.6, 2.6 Hz, 1H) 4.59 (dd, J=7.9, 2.6 Hz, 1H) 4.92 (dd, J=9.7, 2.6 Hz, 1H) 5.07 (t, J=1.2 Hz, 1H) 5.09-5.16 (m, 1H) 5.22 (ddd, J=7.5, 4.8, 2.6 Hz, 1H) 5.69-5.90 (m, 1H).

(R)-1-((3aR,4S,6S,7S,7aS)-6-allyl-7-hydroxytetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1-cyclohexan]-4-yl)ethane-1,2-diol

To a solution of (R)-1-((3aR,4S,6S,7S,7aR)-7-acetoxy-6-allyltetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-4-yl)ethane-1,2-diyldiacetate (11.0 g, 21.7 mmol) in methanol (12 mL) and MTBE (57 mL) was added sodium methoxide solution in MeOH (25 wt %, 7.45 mL, 32.6 mmol) at ambient temperature. After 2.5 h, the reaction mixture was cooled to 10-15° C. Acetic acid (2.0 mL, 35 mmol) was added while keeping the internal temperature below 20° C. The resulting mixture was concentrated in vacuo. Saturated aqueous NaHCO₃ (8%) (38.3 mL) was added and the resulting mixture was extracted four times with EtOAc (191 mL). The combined organic layers were washed with 30% aqueous NaCl (19 mL) and dried over MgSO₄. Filtration, concentration in vacuo, and purification by silica gel column chromatography using a 50-100% gradient of ethyl acetate in n-heptane as eluent provided 6.75 g of the target product as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.33-1.80 (m, 10H) 2.29-2.39 (m, 1H) 2.47-2.56 (m, 1H) 3.58-3.67 (m, 2H) 3.73 (dd, J=11.7, 4.1 Hz, 1H) 3.78 (dd, J=12.0, 3.8 Hz, 1H) 3.83-3.95 (m, 2H) 4.43 (dd, J=8.1, 1.6 Hz, 1H) 4.54 (dd, J=7.9, 3.5 Hz, 1H) 5.03-5.30 (m, 2H) 5.78-5.99 (m, 1H).

(R)-1-((3aR,4S,6S,7S,7aS)-6-allyl-7-hydroxytetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-4-yl)ethane-1,2-diol (1.0 g, 3.18 mmol) was dissolved in acetone (5.0 mL, 68.1 mmol) at ambient temperature. 2,2-Dimethoxypropane (1.369 mL, 11.13 mmol) and p-toluenesulfonic acid monohydrate (0.061 g, 0.318 mmol) were added, and the resulting mixture was stirred for 30 min. Saturated aqueous NaHCO₃ (10 mL) were added, and the resulting mixture was extracted three times with EtOAc (12 mL each time). The combined organic layers were washed with brine (5 mL) and dried over MgSO₄. Filtration followed by concentration in vacuo gave 1.09 g of the target product as a white solid.

(3aR,4S,6S,7S,7aR)-6-allyl-4-((R)-1,2-dihydroxyethyl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-7-yl benzoate

To a solution of (3aR,4S,6S,7S,7aS)-6-allyl-4-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-7-o (1.09 g, 3.075 mmol) in pyridine (5.45 mL) at ambient temperature were added benzoyl chloride (0.714 mL, 6.151 mmol) and 4-dimethylaminopyridine (0.019 g, 0.154 mmol). After complete consumption of the starting material, saturated aqueous NH₄Cl (27 wt %) (15 mL), MTBE (40 mL), and water (5.0 mL) were added. The layers were separated, and the organic layer was washed sequentially with 1M aqueous hydrochloric acid (10 mL, 10.00 mmol), saturated aqueous NaHCO₃ (8%) (5.0 mL), and 30% aqueous NaCl (5.0 mL). The resulting organic layer was dried over MgSO₄, filtered and concentrated in vacuo. The residue (1.1 g) was dissolved in acetic acid (16 mL) and water (4 mL). The resulting mixture was stirred at ambient temperature overnight and then at a temperature between 35 and 40° C. for 24 h. The mixture was then concentrated in vacuo and azeotroped twice with toluene. The residue was purified by silica gel plug purification to give 1.1 g of the target product as a pale yellow solid

(3aS,4R,6S,7S,7aR)-6-allyl-4-formyltetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1-cyclohexan]-7-yl benzoate

(3aR,4S,6S,7S,7aR)-6-allyl-4-((R)-1,2-dihydroxyethyl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-7-yl benzoate (1.1 g, 2.629 mmol) was dissolved in ethyl acetate (11.00 mL) and water (11.00 mL) and cooled to 0° C. Sodium periodate (0.843 g, 3.943 mmol) was added, and the resulting mixture was stirred for 2.5 h at ambient temperature. Additional sodium periodate (0.2 g) was then added. After additional stirring for 2.5 h, the layers were separated. The aqueous layer was extracted twice with EtOAc (11.00 mL), and the combined organic layers were washed with 30% aqueous NaCl (5.50 mL) and dried over MgSO₄. Filtration followed by concentration in vacuo provided 0.98 g of as a foam solid.

(3aR,4S,6S,7S,7aR)-6-allyl-4-((S,E)-1-hydroxy-3-(trimethylsilyl)allyl)tetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1-cyclohexan]-7-yl benzoate

To a solution of (3aS,4R,6S,7S,7aR)-6-allyl-4-formyltetrahydro-3aH-spiro[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-7-yl benzoate (0.98 g) in acetonitrile (7 mL) was added (2-bromovinyl)trimethylsilane (1.941 mL, 12.68 mmol). The resulting solution was degassed for 0.5 h. To another reactor were added chromium(II) chloride (3.12 g, 25.36 mmol), nickel(II) chloride (0.033 g, 0.254 mmol), DMSO (6.86 mL), and MeCN (6.86 mL), and the resulting mixture was cooled to 0-5° C. The aldehyde and vinyl bromide solution was added to the chromium and nickel mixture. The reaction mixture was stirred overnight at a temperature between 5 and 15° C. and then treated with methanol (20.42 mL), water (20.58 mL), and MTBE (24.50 mL). The layers were separated, and the aqueous layer was extracted twice with MTBE (34.3 mL). The combined organic layers were washed twice with 30% aqueous NaCl (19.60 mL) and dried over MgSO₄. Filtration followed by concentration in vacuo provided 0.521 g of the target product as white foam solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.07 (s, 9H) 1.21-1.87 (m, 10H) 2.24-2.33 (m, 1H) 2.34-2.43 (m, 1H) 2.59-2.68 (m, 1H) 3.49 (dd, J=6.6, 2.0 Hz, 1H) 4.28-4.37 (m, 2H) 4.54 (dd, J=8.0, 1.8 Hz, 1H) 4.72 (dd, J=7.8, 2.7 Hz, 1H) 5.02-5.09 (m, 2H) 5.13 (dd, J=9.8, 2.7 Hz, 1H) 5.77-5.93 (m, 1H) 6.07 (dd, J=18.7, 1.6 Hz, 1H) 6.23 (dd, J=19.1, 4.3 Hz, 1H) 7.43-7.48 (m, 2H) 7.57 (d, J=7.4 Hz, 1H) 8.07 (dd, J=8.4, 1.4 Hz, 2H)

(2S,3R,4R,5S,6S)-2-allyl-4,5-dihydroxy-6-((S,E)-1-hydroxy-3-(trimethylsilyl)allyl)tetrahydro-2H-pyran-3-yl benzoate

To (3aR,4S,6S,7S,7aR)-6-allyl-4-((S,E)-1-hydroxy-3-(trimethylsilyl)allyl)tetrahydro-3aH-spirop[[1,3]dioxolo[4,5-c]pyran-2,1′-cyclohexan]-7-ylbenzoate (0.521 g, 1.071 mmol) were added acetic acid (7.8 mL) and water (7.8 mL). The reaction mixture was heated to 90-97° C. for 100 min and concentrated in vacuo. The residue was azeotroped with toluene and purified by silica gel plug to give 0.33 g of the target product as a white foam solid.

(2S,3S,4S,5R,6S)-2-allyl-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-(trimethylsilyl)allyl)tetrahydro-2H-pyran-3-yl benzoate

(2S,3R,4R,5S,6S)-2-allyl-4,5-dihydroxy-6-((S,E)-1-hydroxy-3-(trimethylsilyl)allyl)tetrahydro-2H-pyran-3-yl benzoate (0.33 g) was dissolved in MTBE (4.95 mL) and cooled to 0° C. 2,6-Dimethylpyridine (0.95 mL, 8.1 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (0.84 mL, 3.7 mmol) were added. The resulting mixture was stirred at ambient temperature overnight. Saturated aqueous NH₄Cl (27 wt %) (4.95 mL), MTBE (9.90 mL), and water (3.30 mL) were added. The organic layer was separated and dried over MgSO₄. Filtration, concentration, and purification by silica gel column chromatography using a 0-10% gradient of ethyl acetate in n-heptane as eluent afforded 0.619 g of the target product as an oil.

(2S,3S,4S,5R,6S)-2-allyl-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)tetrahydro-2H-pyran-3-yl benzoate

(2S,3S,4S,5R,6S)-2-allyl-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-(trimethylsilyl)allyl)tetrahydro-2H-pyran-3-yl benzoate (0.510 g, 0.681 mmol) was dissolved in toluene (2.295 mL) and MeCN (4.59 mL) at ambient temperature. To the solution were added tert-butyldimethylsilyl chloride (7.69 mg, 0.051 mmol) and NIS (0.919 g, 4.08 mmol). The reaction mixture was stirred at 28-31° C. for 20 h and cooled to ambient temperature. Toluene (24.29 mL), sodium thiosulfate (1.076 g, 6.806 mmol) and saturated aqueous NaHCO₃ (8%) (5.10 mL) were added, and the resulting mixture was stirred over 2 h at ambient temperature. The layers were separated, and the organic layer was washed twice with 30% aqueous NaCl (7.29 mL) and dried over MgSO₄. Filtration followed by concentration and purification by silica gel column chromatography using a 0-10% gradient of ethyl acetate in n-heptane as eluent provided 467 mg of the target product as a pale yellow oil.

¹H NMR (400 MHz, CDCl₃) δ ppm −0.04-0.27 (m, 18H) 0.89 (br. s., 9H) 0.90 (br. s., 9H) 0.96 (s, 9H) 2.22-2.53 (m, 2H) 3.24-3.69 (m, 1H) 3.76-4.50 (m, 4H) 4.95-5.35 (m, 3H) 5.71-5.90 (m, 1H) 6.36 (d, J=14.9 Hz, 1H) 6.50-6.73 (m, 1H) 7.33-7.46 (m, 1H) 7.48-7.60 (m, 2H) 7.96-8.15 (m, 2H).

(S)-5-(((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane

3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propan-1-ol (1.00 g, 1.175 mmol) was dissolved in dichloromethane (7.00 mL) at ambient temperature. Imidazole (0.240 g, 3.52 mmol) and chlorotriethylsilane (0.300 mL, 1.76 mmol) were added, and the resulting mixture was stirred at ambient temperature for 1 h., at which time a saturated aqueous NH₄Cl (27 wt %) (12.00 mL, 64.205 mmol) was added, and the resulting mixture was extracted with MTBE (15.00 mL, 125.924 mmol). The combined organic layers were washed with 30% aqueous NaCl (10.00 mL, 52.578 mmol) and dried over MgSO₄. Concentration and azeotroping with toluene provided 1.177 g of the target product as an oil.

Methyl (R)-2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-(phenylsulfonyl)acetate

(S)-5-(((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (1.177 g, 1.17 mmol) was dissolved in THF (11.3 mL) and cooled to 0° C. n-BuLi (1.6 M, 0.95 mL, 1.5 mmol) was added. The resulting solution was stirred for 20 min at 0° C. and cooled to −78° C. Methyl chloroformate (0.14 mL, 1.8 mmol) was added, and the resulting solution was stirred for 1.5 h with warming to −40° C. Saturated aqueous NH₄Cl (27 wt %) (10 mL), water (5 mL) and MTBE (11 mL) were added, and the resulting mixture was warmed to ambient temperature. The layers were separated, and the organic layer was washed with saturated aqueous NaCl (4 mL) and dried over MgSO₄. Filtration followed by concentration in vacuo provided 1.267 g of the target product as colorless oil.

methyl 2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)acetate

(S)-methyl 2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-(phenylsulfonyl)acetate (1.267 g, 1.176 mmol) was dissolved in methanol (36.1 mL) at ambient temperature. Magnesium (0.286 g, 11.8 mmol) was added, and the resulting mixture was stirred at ambient temperature. Additional magnesium (0.56 g) and methanol (32 mL) were added over 20 h. Once the starting material was consumed, the reaction mixture was cooled below 10° C. and treated with sodium phosphate, monobasic (4.66 g, 38.8 mmol). The resulting mixture was concentrated in vacuo. To the residue were added MTBE (36.1 mL), saturated aqueous NH₄Cl (27 wt %) (18.0 mL), and water (12.0 mL). The resulting mixture was stirred at ambient temperature and filtered through a Celite® pad. The layers were separated, and the aqueous layer was extracted with MTBE (24.0 mL). The combined organic layers were washed with 30% aqueous NaCl (12.0 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was dissolved in dichloromethane (12.0 mL) at ambient temperature and treated with imidazole (0.400 g, 5.88 mmol) and chlorotriethylsilane (0.59 mL, 3.53 mmol). After 2 h at ambient temperature, the reaction was quenched with saturated aqueous NH₄Cl solution (10 mL). The resulting mixture was extracted with MTBE (30 mL). The organic layer was washed with 30% aqueous NaCl (10 mL), dried over MgSO₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a 5-20% gradient of ethyl acetate in n-heptane as eluent to give 0.42 g of the target product as colorless oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.03 (s, 3H) 0.04 (s, 3H) 0.06 (s, 3H) 0.07 (s, 3H) 0.55-0.62 (m, 6H) 0.87-0.88 (m, 9H) 0.88 (s, 9H) 0.92-0.97 (m, 9H) 1.07 (d, J=6.6 Hz, 3H) 1.43-1.70 (m, 8H) 1.79 (s, 2H) 1.92-2.02 (m, 2H) 2.09-2.19 (m, 1H) 2.20-2.45 (m, 6H) 2.59-2.69 (m, 1H) 3.29 (s, 3H) 3.41 (d, J=3.9 Hz, 1H) 3.46-3.65 (m, 5H) 3.67-3.73 (m, 1H) 3.69 (s, 3H) 3.74-3.81 (m, 2H) 3.83-3.91 (m, 1H) 3.95-4.06 (m, 1H) 4.34-4.43 (m, 1H) 4.79 (d, J=1.6 Hz, 1H) 4.82 (d, J=2.0 Hz, 1H) 4.87 (s, 1H) 4.96 (d, J=2.0 Hz, 1H).

methyl 2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)acetate

A solution of oxalyl chloride (0.2 M, 0.10 mL, 0.20 mmol) in dichloromethane was diluted with dichloromethane (1.0 mL) and cooled to −78° C. A solution of DMSO (0.030 mL, 0.419 mmol) in dichloromethane (0.300 mL, 4.66 mmol) followed by a solution of methyl 2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)acetate (0.10 g, 0.113 mmol) in dichloromethane (0.500 mL) was added. The resulting solution was stirred for 30 min at −50° C., cooled to −78° C. and treated with triethylamine (0.095 mL, 0.679 mmol). The mixture was warmed to ambient temperature over 1 h, diluted with MTBE (15 mL), and washed with saturated aqueous NH₄Cl solution (5 mL) and 30% aqueous NaCl (3 mL). The organic layer was dried over MgSO₄, filtered, and concentrated in vacuo. The residue was filtered through a silica gel plug with MTBE. Concentration of the filtrate in vacuo provided 89 mg of the target product as an oil.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.04 (s, 3H) 0.04 (s, 3H) 0.06 (s, 3H) 0.07 (s, 3H) 0.88 (s, 9H) 0.89 (s, 9H) 1.08 (d, J=6.3 Hz, 3H) 1.42-1.69 (m, 5H) 1.74-1.85 (m, 4H) 1.93-2.03 (m, 2H) 2.10-2.19 (m, 1H) 2.22-2.32 (m, 3H) 2.34-2.46 (m, 2H) 2.47-2.62 (m, 2H) 2.63-2.73 (m, 1H) 3.29 (s, 3H) 3.42 (d, J=3.5 Hz, 1H) 3.50 (d, J=5.1 Hz, 2H) 3.56 (d, J=5.9 Hz, 1H) 3.67-3.73 (m, 1H) 3.70 (s, 3H) 3.78 (d, J=5.5 Hz, 2H) 3.84-3.91 (m, 1H) 4.04 (quin, J=6.4 Hz, 1H) 4.34 (d, J=6.6 Hz, 1H) 4.79-4.81 (m, 1H) 4.84 (d, J=2.3 Hz, 1H) 4.88 (s, 1H) 4.98 (d, J=2.3 Hz, 1H) 9.79 (t, J=1.4 Hz, 1H)

(2S,3S,4S,5R,6S)-2-allyl-6-((1S,E)-6-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5- ((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxyhex-2-en-1-yl)-4,5-bis((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-3-yl benzoate

(S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide (688 mg, 2.32 mmol) was dissolved in acetonitrile (4 mL) and purged with nitrogen for 30 min. Chromous chloride (285 mg, 2.32 mmol) and triethylamine (320 μL, 2.32 mmol) were added, and the resulting dark green mixture was stirred at 35° C. for 1 h. In another reactor, methyl 2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-oxopropyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)acetate (89 mg, 0.116 mmol) and (2S,3S,4S,5R,6S)-2-allyl-4,5-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)tetrahydro-2H-pyran-3-yl benzoate (107 mg, 0.133 mmol) were dissolved in THF (870 μL) and acetonitrile (680 μL) and purged with nitrogen for 10 min. Nickel(II) chloride complex with 2,9-dimethyl-1,10-phenanthroline (7.84 mg, 0.023 mmol) followed by the sulfonamide complex solution prepared above was added. The resulting mixture was stirred vigorously for 5 h at 15-23° C. and diluted with n-heptane (6.5 mL). The resulting mixture was filtered through a Celite® pad, which was then rinsed with n-heptane (10 mL) and acetonitrile (10 mL). The layers were separated, and the bottom acetonitrile layer was extracted twice with n-heptane (7 mL each). The combined n-heptane layers were washed twice with acetonitrile (5 mL each) and concentrated in vacuo. The residue was purified by silica gel column chromatography using a 10-33% gradient of ethyl acetate in n-heptane as eluent to give 99 mg of the target product as white foam solid.

(2S,3S,4S,5R,6S)-2-allyl-6-((S,E)-6-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-oxohex-2-en-1-yl)-4,5-bis((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-3-yl benzoate

To a solution of (2S,3S,4S,5R,6S)-2-allyl-6-((1 S,E)-6-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxyhex-2-en-1-yl)-4,5-bis((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-3-yl benzoate (0.284 g, 0.197 mmol) in dichloromethane (5.7 mL) at ambient temperature were added sodium bicarbonate (83 mg, 0.98 mmol) and Dess-Martin periodinane (250 mg, 0.59 mmol). After being stirred over 2 h at ambient temperature, the reaction mixture was diluted with MTBE (8.5 mL). Water (2.8 mL), sodium thiosulfate (0.155 mg, 0.983 mmol), and saturated aqueous NaHCO₃ (8%) (2.84 mL) were added, and the resulting mixture was stirred for 30 min. The layers were separated, and the organic layer was washed twice with 30% aqueous NaCl (1.4 mL each time) and dried over MgSO₄. Filtration and concentration in vacuo provided 270 mg of the target product as white foam.

¹H NMR (400 MHz, CDCl₃) δ ppm −0.13-0.23 (m, 30H) 0.87 (s, 9H) 0.88 (br. s, 18H) 0.90-0.91 (m, 9H) 0.96 (s, 9H) 1.07 (d, J=6.3 Hz, 3H) 1.41-1.70 (m, 6H) 1.72-1.86 (m, 4H) 1.93-2.03 (m, 2H) 2.09-2.19 (m, 1H) 2.20-2.56 (m, 7H) 2.57-2.80 (m, 3H) 3.29 (s, 3H) 3.41 (d, J=3.5 Hz, 2H) 3.43-3.55 (m, 4H) 3.56 (m, J=5.5 Hz, 1H) 3.65-3.73 (m, 1H) 3.69 (s, 3H) 3.74-3.82 (m, 2H) 3.84-3.90 (m, 1H) 3.92-4.15 (m, 4H) 4.30-4.41 (m, 1H) 4.59-4.70 (m, 1H) 4.79 (d, J=1.2 Hz, 1H) 4.81-4.85 (m, 1H) 4.87 (s, 1H) 4.95-5.00 (m, 1H) 5.05-5.29 (m, 2H) 5.62-5.83 (m, 1H) 6.27 (d, J=15.2 Hz, 1H) 6.65-6.85 (m, 1H) 7.34-7.48 (m, 2H) 7.50-7.60 (m, 1H) 7.92-8.14 (m, 2H)

(2S,3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-6-yl benzoate

(2S,3S,4S,5R,6S)-2-allyl-6-((S,E)-6-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-oxohex-2-en-1-yl)-4,5-bis((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-3-yl benzoate (0.270 g, 0.187 mmol) was dissolved in N,N-dimethylacetamide (4.3 mL), and THF (10.8 mL) at ambient temperature. A mixture of tetrabutylammonium fluoride (1.0 M, 1.9 mL, 1.9 mmol) and imidazole hydrochloride (0.098 g, 0.936 mmol) was added, and the resulting solution was stirred at ambient temperature for 20 h. Water (5.4 mL) and toluene (11 mL) were added and the layers were separated. The aqueous layer was extracted twice with a mixture of toluene (11 mL) and THF (11 mL). The combined organic layers were washed with 30% aqueous NaCl (5.4 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was azeotroped with a mixture of acetonitrile (3.2 mL) and water (1.1 mL) three times to give 0.26 g of brown oil. The crude product was dissolved in dichloromethane (5.0 mL) and treated with DBU (0.050 mL, 0.332 mmol) for 1 h at ambient temperature. Pyridinium p-toluenesufonate (496 mg, 1.98 mmol) was added, and the resulting mixture was stirred for 3 h at ambient temperature. The reaction mixture was purified by silica-gel column chromatography using a 0-100% gradient of acetonitrile in ethyl acetate as eluent to afford 44 mg of the target product.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.08 (d, J=6.6 Hz, 3H) 1.43-2.49 (m, 23H) 2.68 (ddd, J=15.7, 6.5, 1.6 Hz, 1H) 3.32 (s, 3H) 3.46-3.57 (m, 3H) 3.61-3.66 (m, 1H) 3.69 (s, 3H) 3.76 (dd, J=9.0, 3.9 Hz, 1H) 3.83 (dt, J=7.7, 5.3 Hz, 1H) 3.90-4.01 (m, 2H) 4.03 (d, J=7.0 Hz, 1H) 4.21 (dd, J=6.6, 4.3 Hz, 1H) 4.30 (dd, J=6.4, 4.5 Hz, 1H) 4.35-4.40 (m, 1H) 4.64 (dd, J=4.1, 2.1 Hz, 1H) 4.66-4.69 (m, 1H) 4.70-4.80 (m, 3H) 4.81 (d, J=1.6 Hz, 1H) 4.85 (d, J=1.6 Hz, 1H) 4.86 (s, 1H) 4.97 (d, J=2.0 Hz, 1H) 5.00-5.04 (m, 1H) 5.06 (d, J=1.6 Hz, 1H) 5.80-5.99 (m, 1H) 7.41-7.46 (m, 2H) 7.54-7.59 (m, 1H) 8.04 (dd, J=8.4, 1.4 Hz, 2H).

methyl 2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)acetate

(3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-(2-methoxy-2-oxoethyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-6-yl benzoate (48.7 mg, 0.057 mmol) was dissolved in THF (1.5 mL) and cooled to 0° C. A solution of sodium methoxide in methanol (25 wt %, 17 μL, 0.074 mmol) was added, and the resulting solution was stirred at ambient temperature for 1 h. Acetic acid (6.54 μL, 0.114 mmol) was added, and solvents were removed with a stream of nitrogen. The residue was azeotroped with toluene and dissolved in DMF (1.5 mL) at ambient temperature. To the resulting solution were added imidazole (58.4 mg, 0.857 mmol), chlorotriethylsilane (0.096 mL, 0.572 mmol), and 4-dimethylaminopyridine (7.0 mg, 0.057 mmol). The resulting mixture was stirred at ambient temperature for 2 days and then treated with saturated aqueous NaHCO₃ (8%) (3.0 mL). The resulting mixture was extracted twice with MTBE (12 mL). The combined organic layers were washed with 30% aqueous NaCl (4.0 mL) and dried over MgSO₄. Filtration followed by concentration and purification by silica gel column chromatography using a 10-33% gradient of ethyl acetate in n-heptane as eluent provided 110 mg of the target product.

2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((2S,3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)ethan-1-ol

methyl 2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)- 7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)acetate (110 mg) was dissolved in THF (3.0 mL) and cooled to 0° C. A solution of lithium aluminum hydride in THF (1.0 M, 0.11 mL, 0.11 mmol) was added, and the resulting solution was stirred for 30 min. Saturated aqueous NH₄Cl (27 wt %) (3.0 mL) and water (1 mL) were added, and the resulting mixture was extracted twice with MTBE (6 mL each time). The combined organic layers were washed with 30% aqueous NaCl (4.0 mL) and dried over MgSO₄. Filtration followed by concentration and purification by silica gel column chromatography using a 25-50% gradient of ethyl acetate in n-heptane as eluent provided 26.6 mg of the target product.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.56-0.65 (m, 18H) 0.91-0.99 (m, 27H) 1.07 (d, J=6.2 Hz, 3H) 1.46-1.83 (m, 12H) 1.89-2.17 (m, 8H) 2.20-2.31 (m, 2H) 2.51-2.59 (m, 1H) 2.60-2.69 (m, 1H) 3.22 (dd, J=9.4, 2.3 Hz, 1H) 3.30 (s, 3H) 3.45 (dd, J=4.3, 3.1 Hz, 1H) 3.50-3.62 (m, 3H) 3.68-3.78 (m, 3H) 3.78-3.84 (m, 1H) 3.84-3.90 (m, 1H) 3.90-3.96 (m, 1H) 3.97-4.05 (m, 2H) 4.18 (dd, J=6.6, 4.7 Hz, 1H) 4.29 (dd, J=4.1, 2.1 Hz, 1H) 4.30-4.36 (m, 1H) 4.37-4.43 (m, 1H) 4.58 (t, J=4.5 Hz, 1H) 4.66 (t, J=4.7 Hz, 1H) 4.79-4.80 (m, 1H) 4.83 (d, J=2.0 Hz, 1H) 4.88 (s, 1H) 4.96 (d, J=2.0 Hz, 1H) 5.07 (d, J=10.2 Hz, 1H) 5.14 (d, J=1.2 Hz, 1H) 5.91 (dddd, J=17.3, 10.1, 7.7, 5.9 Hz, 1H)

2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)acetaldehyde

To a solution of 2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)ethanol (13.3 mg, 0.013 mmol) in dichloromethane (1.0 mL) at ambient temperature were added sodium bicarbonate (10.5 mg, 0.125 mmol) and Dess-Martin periodinane (26.5 mg, 0.063 mmol). After being stirred for 40 min, the reaction mixture was treated with MTBE (6.0 mL), water (3.0 mL) and sodium thiosulfate (15.82 mg, 0.10 mmol). After 10 min of being stirred, the layers were separated, and the organic layer was washed twice with 30% aqueous NaCl (2.0 mL) and dried over MgSO₄. Concentration in vacuo provided 12 mg of the target product.

1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)pent-4-en-2-ol

2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)acetaldehyde (12 mg, 0.011 mmol) was dissolved in THF (1.0 mL) and cooled to 0° C. A solution of allylmagnesium chloride in THF (2.0 M, 0.017 mL, 0.034 mmol) was added. The resulting solution was stirred for 20 min and then treated with saturated aqueous NH₄Cl (27 wt %) (3.0 mL). The resulting mixture was extracted with MTBE (10 mL). The organic layer was washed twice with 30% aqueous NaCl (2.0 mL), dried over MgSO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a 20-33% gradient of ethyl acetate in n-heptane as eluent provided 11.7 mg of the target product.

1-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)pent-4-en-2-ol (11.7 mg, 10.60 μmol) was dissolved in toluene (10 mL) and heated to 50° C. Hoveyda-Grubbs 2nd Generation Catalyst (1.333 mg, 2.12 μmol) was added, and the resulting solution was stirred for 3 h at a temperature between 68-73° C. The reaction mixture was cooled to ambient temperature and purified by silica gel column chromatography using a 20-33% gradient of ethyl acetate in n-heptane as eluent to provide 7.7 mg of the target product. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.56-0.68 (m, 18H) 0.85-1.02 (m, 27H) 1.08 (d, J=6.2 Hz, 3H) 1.28-2.35 (m, 23H) 2.39-2.84 (m, 3H) 3.17 (ddd, J=9.5, 5.6, 2.1 Hz, 1H) 3.31 (s, 3H) 3.41-3.64 (m, 4H) 3.65-4.07 (m, 6H) 4.17 (d, J=6.6 Hz, 1H) 4.28 (dd, J=4.1, 2.1 Hz, 1H) 4.31-4.41 (m, 3H) 4.56-4.69 (m, 2H) 4.79 (s, 1H) 4.83 (br. s., 1H) 4.92 (s, 1H) 4.96 (d, J=2.3 Hz, 1H) 5.45-5.61 (m, 1H) 5.62-5.76 (m, 1H)

The starting material (7.7 mg, 7.158 μmol) was dissolved in dichloromethane (0.70 mL) and treated with sodium bicarbonate (6.01 mg, 0.072 mmol) and Dess-Martin periodinane (12.14 mg, 0.029 mmol). After being stirred at ambient temperature for 1 h, the reaction mixture was diluted with MTBE (5.0 mL) and water (3.0 mL). Sodium thiosulfate (11.32 mg, 0.072 mmol) was added and the resulting mixture was stirred at for 20 min. The layers were separated and the organic layer was washed with 30% aqueous NaCl (1.0 mL) and dried over MgSO₄. Filtration followed by concentration and purification by silica gel column chromatography using n-heptane/ethyl acetate (2/1) as eluent afforded 6.8 mg of the target product as a film.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.55-0.65 (m, 18H) 0.91-1.02 (m, 27H) 1.08 (d, J=6.6 Hz, 3H) 1.40-2.33 (m, 20H) 2.49-2.67 (m, 4H) 3.03 (dd, J=15.6, 7.8 Hz, 1H) 3.08-3.14 (m, 1H) 3.16 (dd, J=9.4, 2.0 Hz, 1H) 3.30 (d, J=3.1 Hz, 1H) 3.35 (s, 3H) 3.44-3.57 (m, 3H) 3.73-3.87 (m, 3H) 3.87-3.94 (m, 1H) 3.97-4.00 (m, 1H) 4.18 (dd, J=6.6, 4.3 Hz, 1H) 4.29 (dd, J=4.1, 2.1 Hz, 1H) 4.32-4.44 (m, 3H) 4.59-4.66 (m, 2H) 4.79 (s, 1H) 4.83 (s, 1H) 4.91 (s, 1H) 4.98 (s, 1H) 5.57 (dt, J=15.2, 7.0 Hz, 1H) 5.69 (dt, J=14.8, 6.2 Hz, 1H)

To a solution of compound 7 (3.4 mg, 3.167 μmol) in THF (0.5 mL) at ambient temperature was added TBAF (1.0 M, 0.025 mL, 0.025 mmol). The resulting solution was stirred for 25 h at ambient temperature and then purified by silica gel column chromatography using a 0-100% gradient of acetonitrile in ethyl acetate as eluent to provide 1.6 mg of the target product. The structure was confirmed by comparison of the ¹H NMR spectrum to that of an authentic sample.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.10 (d, J=6.6 Hz, 1H) 1.19-1.83 (m, 8H) 1.92-2.36 (m, 12H) 2.39-2.58 (m, 3H) 2.72 (dd, J=16.0, 9.8 Hz, 1H) 2.82-2.92 (m, 2H) 2.94-3.02 (m, 1H) 3.29 (d, J=3.1 Hz, 1H) 3.44 (s, 3H) 3.51-3.69 (m, 4H) 3.86 (dt, J=9.0, 3.1 Hz, 1H) 3.89-3.99 (m, 3H) 4.03 (dd, J=6.3, 4.3 Hz, 1H) 4.08-4.16 (m, 1H) 4.19 (dd, J=6.6, 4.7 Hz, 1H) 4.26-4.41 (m, 3H) 4.61 (t, J=4.7 Hz, 1H) 4.69 (t, J=4.3 Hz, 1H) 4.82 (d, J=1.6 Hz, 1H) 4.89 (br. s., 1H) 4.93 (br. s, 1H) 5.07 (d, J=2.0 Hz, 1H)

Example 5 Preparation of a Compound of Formula (ID) Through C.2-C.3 Macrocyclization

Methyl 2-((2S,3S,4R,5R)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((2S,3aR,4aR,5R,6S,7S,8aR,8bS)-7-(3-hydroxypropyl)-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)acetate

To a solution of methyl 2-((2S,3S,4R,5R)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-allyl-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-4-methoxytetrahydrofuran-3-yl)acetate (10 mg, 9.16 μmol) in THF (0.2 mL) was added the freshly prepared solution of disiamylborane in THF (0.45 M, 0.041 mL, 0.018 mmol) at 0° C. The resulting solution was warmed to ambient temperature. After 1 h, 2 h, and 4 h, additional diisoamylborane solution was added (each time 40 μL). After being stirred for 2 h, the reaction mixture was diluted with MTBE (1.0 mL) and cooled down to 0° C. 3M Sodium hydroxide (0.10 mL, 0.30 mmol) and 30% hydrogen peroxide (0.10 mL, 0.979 mmol) were added. The resulting mixture was stirred at ambient temperature for 2 h and treated with saturated aqueous NH₄Cl solution (2 m) and MTBE (2 mL). The layers were separated, and the aqueous layer was extracted with MTBE (3 mL). The combined organic layers were washed with saturated aqueous NaHSO₃ (1 mL) and 30% aqueous NaCl (1 mL) and dried over MgSO₄. Filtration followed by concentration in vacuo and purification by silica gel column chromatography using a 20-33% gradient of ethyl acetate in n-heptane as eluent provided 3.6 mg of the target product.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.53-0.66 (m, 18H) 0.91-0.99 (m, 27H) 1.08 (d, J=6.6 Hz, 3H) 1.17-1.24 (m, 1H) 1.36 (m, 2H) 1.65-1.85 (m, 9H) 1.88-2.03 (m, 6H) 2.14 (d, J=12.9 Hz, 2H) 2.21-2.32 (m, 3H) 2.35 (m, 1H) 2.40 (m, 1H) 2.59-2.69 (m, 1H) 3.19 (dd, J=9.6, 2.1 Hz, 1H) 3.29 (s, 3H) 3.43 (d, J=3.5 Hz, 1H) 3.49 (dd, J=10.2, 5.1 Hz, 2H) 3.56 (dd, J=10.9, 6.6 Hz, 1H) 3.62-3.69 (m, 2H) 3.69-3.72 (m, 4H) 3.78 (dd, J=9.0, 4.7 Hz, 1H) 3.80-3.90 (m, 3H) 3.97-4.06 (m, 2H) 4.18 (dd, J=6.8, 4.5 Hz, 1H) 4.24-4.31 (m, 2H) 4.34-4.41 (m, 1H) 4.57 (t, J=4.7 Hz, 1H) 4.68 (t, J=4.7 Hz, 1H) 4.80 (s, 1H) 4.82 (s, 1H) 4.87 (s, 1H) 4.96 (d, J=2.0 Hz, 1H).

dimethyl (3-((2S,3S,4R,5R)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((2S,3aR,4aR,5R,6S,7S,8aR,8bS)-7-(3-hydroxypropyl)-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)-2-oxopropyl)phosphonate

To a solution of dimethyl methylphosphonate (11 μL, 0.097 mmol) in THF (0.50 mL) was added n-BuLi (1.6 M, 0.061 mL, 0.097 mmol) at −78° C., and the resulting solution was stirred for 40 min at −78° C. A solution of methyl 2-((2S,3S,4R,5R)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-(3-hydroxypropyl)-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)acetate (3.6 mg, 3.244 μmol) in THF (0.50 mL) was then added. The reaction mixture was stirred for 1.5 h at −78° C. and treated with saturated aqueous NH₄Cl solution (2 mL). The resulting mixture was diluted with ethyl acetate (2 mL) and warmed to ambient temperature. The layers were separated, and the aqueous layer was extracted with ethyl acetate (5 mL). The combined organic layers were dried over MgSO₄, filtered, concentrated, and purified by silica gel column chromatography using Heptane/EtOAc (1/1), EtOAc, EtOAc/MeCN (1/1), and DCM/MeOH (10/1) as eluents to provide 1 mg of the target product.

MS m/z 1202.2 [M+H]⁺, 1203.2, 1204.2. ¹H NMR (400 MHz, CDCl₃) δ ppm 0.55-0.66 (m, 18H) 0.92-0.99 (m, 27H) 1.07 (d, J=6.6 Hz, 3H) 1.15-2.18 (m, 22H) 2.20-2.30 (m, 1H) 2.64-2.70 (m, 1H) 3.07 (d, J=9.8 Hz, 1H) 3.13 (d, J=9.8 Hz, 1H) 3.16-3.24 (m, 1H) 3.33 (dd, J=10.2, 3.5 Hz, 1H) 3.33 (s, 3H) 3.48-3.59 (m, 4H) 3.63-3.72 (m, 2H) 3.73-3.88 (m, 4H) 3.77-3.79 (m, 3H) 3.81 (s, 3H) 3.99-4.06 (m, 2H) 4.16-4.21 (m, 1H) 4.26-4.31 (m, 2H) 4.34-4.40 (m, 1H) 4.57 (t, J=4.3 Hz, 1H) 4.68 (t, J=4.7 Hz, 1H) 4.79 (s, 1H) 4.84 (br. s, 1H) 4.86 (s, 1H) 4.97 (br. s, 1H)

Dimethyl(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((triethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(2-((2S,5S)-5-(2-((3aR,4aR,5R,6S,7S,8aR,8bS)-7-(3-hydroxypropyl)-6-((triethylsilyl)oxy)octahydro-2H-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyran-2-yl)ethyl)-3-methylenetetrahydrofuran-2-yl)ethyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)-2-oxopropyl)phosphonate (1 mg, 0.832 μmol) was dissolved in dichloromethane and treated with sodium bicarbonate (1.4 mg, 0.017 mmol) and Dess-Martin periodinane (3.5 mg, 8.3 μmol) at ambient temperature. After 2 h, the reaction mixture was diluted with MTBE (1 mL) and water (0.5 mL). Sodium thiosulfate (3 mg) was added, and the resulting mixture was stirred for 20 min at ambient temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The residue was diluted with toluene and filtered through a silica gel plug, which was then rinsed with EtOAc. The filtrate was concentrated in vacuo, and the resulting residue was dissolved in THF (1.0 mL). A slurry mixture of zinc trifluoromethanesulfonate (2.4 mg, 0.0067 mmol), TEA (3 μL, 0.020 mmol), and TMEDA (0.5 μL, 0.0033 mmol) in THF (2 mL) was added. The resulting reaction mixture was stirred at ambient temperature for 1 day and treated with MTBE (6 mL) and 30% aqueous NaCl (2 mL). The organic layer was separated and washed with 30% aqueous NaCl (1.5 mL). Drying, filtration, and concentration in vacuo gave the target product. MS m/z 1073.6 [M+H]⁺. The crude macrocyclic product was dissolved in THF (0.5 mL) at ambient temperature and treated with 1.0 M TBAF in THF (0.020 mL, 0.02 mmol). After stirring at ambient temperature overnight, formation of the target product was confirmed by LCMS analysis with an authentic sample (retention time and MS data). MS m/z 731.6 [M+H]⁺, 753.6 [M+Na]⁺.

Example 6 Preparation of a Compound of Formula (VIIB)

(4R)-4-((tert-butyldimethylsilyl)oxy)-7-hydroxy-N-methoxy-N,2-dimethylheptanamide

A solution of (4R)-4-((tert-butyldimethylsilyl)oxy)-N-methoxy-N,2-dimethyl-7-oxoheptanamide (27 g, 81.4 mmol) in methanol (203 mL) was cooled to 0° C. and treated with NaBH₄ (1.54 g, 40.7 mmol), which was added portion wise over 30 min, while maintaining the internal temperature below 10° C. The reaction mixture was stirred at 0° C. for 2 h and quenched with saturated aqueous NH₄Cl (67.5 mL). After stirring at room temperature for 20 min, the mixture was diluted with MTBE (189 mL). The organic layer was separated, and the aqueous layer was extracted with MTBE (50 mL). The organic layers were combined, washed with brine (47.3 mL), and concentrated in vacuo. The residue was filtered through silica gel pad (ca. 40 g), which was rinsed with ethyl acetate/n-heptane=1/1 (300 mL). The filtrate was concentrated in vacuo to give the title compound (26 g, 96%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (s, 6H), 0.86 (s, 9H), 1.12 (d, 3H), 1.42-1.68 (m, 6H), 1.96 (m, 1H), 3.18 (s, 3H), 3.62 (m, 2H), 3.69 (s, 3H), 3.75 (m, 1H).

(4R)-4-((tert-butyldimethylsilyl)oxy)-7-(methoxy(methyl)amino)-6-methyl-7-oxoheptyl pivalate

A solution of (4R)-4-((tert-butyldimethylsilyl)oxy)-7-hydroxy-N-methoxy-N,2-dimethylheptanamide (26 g, 78.0 mmol) in CH₂Cl₂ (130 mL) was cooled to 0° C. and treated with triethylamine (19.56 mL, 140.3 mmol), TMEDA (1.18 mL, 7.80 mmol), and pivaloyl chloride (PvCl) (10.6 mL, 85.8 mmol). After stirring at room temperature for 15 h, the mixture was treated with PvCl (0.96 mL, 7.8 mmol) and triethylamine (5.43 mL, 39.0 mmol) and stirred at rt for another 5 h. The reaction was quenched with water (260 mL). The organic layer was separated, and the aqueous layer was extracted with MTBE (260 mL). The organic layers were combined, washed with brine, and dried over MgSO₄ to give the title compound (32.07 g, 99%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (s, 6H), 0.86 (s, 9H), 1.12 (d, 3H), 1.18 (s, 9H), 1.40-1.55 (m, 4H), 1.68 (m, 2H), 1.92 (m, 1H), 3.17 (s, 3H), 3.69 (m, 4H), 4.03 (t, 2H).

(4R)-4-((tert-butyldimethylsilyl)oxy)-6-methyl-7-oxooctyl pivalate

A solution of (4R)-4-((tert-butyldimethylsilyl)oxy)-7-(methoxy(methyl)amino)-6-methyl-7-oxoheptyl pivalate (32.07 g, 76.79 mmol) in THF (96 mL) was cooled to −20° C. and treated with 3 M MeMgCl in THF (30.7 mL, 92.1 mmol) over 10 min, while maintaining the internal temperature below −10° C. The mixture was warmed up to 0° C. over 2 h and stirred at 0° C. for 13 h. Additional 3 M MeMgCl in THF (5.12 mL, 15.4 mmol) was added and stirring was continued at 0° C. for another 5 h. The reaction was quenched with saturated aqueous NH₄Cl (80 mL) and extracted twice with MTBE (96 mL). The organic layers were combined, dried over MgSO₄ and concentrated in vacuo to give the title compound (28.64 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (s, 6H), 0.86 (s, 9H), 1.10 (d, 3H), 1.19 (s, 9H), 1.34 (m, 1H), 1.50 (m, 2H), 1.64 (m, 2H), 1.88 (m, 1H), 2.13 (s, 3H), 2.68 (m, 1H), 3.68 (m, 1H), 4.03 (t, 2H).

(4R)-4-((tert-butyldimethylsilyl)oxy)-6-methyl-7-(((trifluoromethyl)sulfonyl)oxy)oct-7-en-1-yl pivalate

A mixture of (4R)-4-((tert-butyldimethylsilyl)oxy)-6-methyl-7-oxooctyl pivalate (15.0 g, 40.3 mmol) and 1,1,1-trifluoro-N-phenyl-N-(trifluoromethyl)sulfonyl methanesulfonamide (21.6 g, 60.4 mmol) in THF (150 mL) was cooled to −20° C. and treated with 0.5 M KHMDS in toluene (105 mL, 52.3 mmol) over 20 min, while maintaining the internal temperature below −20° C. The mixture was stirred at −20° C. for 1 h. Additional 0.5 M KHMDS in toluene (8.05 mL, 4.03 mmol) was added, and stirring was continued at −20° C. for another 1 h. The reaction was quenched with saturated aqueous NH₄Cl (105 mL) and extracted twice with n-heptane (105 mL). The organic layers were combined, washed with brine, and concentrated in vacuo. The residue was treated with n-heptane (80 mL) and aged in a freezer (−20° C.) overnight. The precipitate was filtered and rinsed with n-heptane. The filtrate was concentrated in vacuo and purified by column chromatography (ethyl acetate/n-heptane=1/20 to 1/10) to give the title compound (14.25 g, 70%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (d, 6H), 0.86 (s, 9H), 1.15 (d, 3H), 1.18 (s, 9H), 1.40-1.55 (m, 4H), 1.6-1.71 (m, 2H), 2.54 (m, 1H), 3.74 (m, 1H), 4.03 (t, 2H), 4.90 (d, 1H), 5.09 (d, 1H).

(R)-4-((tert-butyldimethylsilyl)oxy)-6-methylocta-6,7-dien-1-yl pivalate

A mixture of Pd₂(dba)₃ (7.3 mg, 7.9 μmol) and (S)-(−)-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl (0.015 g, 0.032 mmol) was purged with nitrogen and treated with n-heptane (2.0 mL). The mixture was stirred at 50° C. for 4.5 h. After cooling to room temperature (rt), the mixture was filtered through Celite® pad to remove catalyst, and the Celite® pad was rinsed with n-heptane. After concentration, the residue was purified by column chromatography (ethyl acetate/n-heptane=1/20 to 1/10) to give the title compound (130 mg, 93%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (s, 6H), 0.84 (s, 9H), 1.18 (s, 9H), 1.40-1.75 (m, 4H), 1.68 (t, 3H), 2.02-2.17 (m, 2H), 3.80 (m, 1H), 4.03 (t, 2H), 4.55 (m, 2H).

(5S)-9-((tetrahydro-2H-pyran-2-yl)oxy)non-1-en-7-yn-5-ol

A solution of tetrahydro-2-(2-propynyloxy)-2H-pyran (27 g, 192.6 mmol) in THF (270 mL) was cooled to −78° C. and treated with 2 M n-BuLi in cyclohexane (99 mL, 198.4 mmol) over 30 min, while maintaining the internal temperature below −65° C. After stirring for 40 min at −78° C., to the mixture was added BF₃.OEt₂ (25.1 mL, 198.4 mmol) over 5 min, the resulting mixture was stirred at −78° C. for 15 min. A solution of (S)-2-(but-3-en-1-yl)oxirane (20.79 g, 211.9 mmol) in THF (54.0 mL) was added over 30 min, while maintaining the internal temperature below −65° C., and stirring was continued at −78° C. for 1 h. The reaction was quenched with saturated aqueous NH₄Cl (270 mL) and warmed to rt. The organic layer was separated and the aqueous layer was extracted with MTBE (270 mL). The organic layers were combined, washed with saturated aqueous NaHCO₃ (81 mL) and brine (80 mL), and dried over MgSO₄ to give the title compound (40.1 g, 87%). ¹H NMR (400 MHz, CDCl₃) δ 1.45-1.88 (m, 7H), 2.00-2.30 (m, 3H), 2.34-2.50 (m, 2H), 3.51 (m, 1H), 3.70-3.88 (m, 2H), 4.25 (m, 2H), 4.80 (m, 1H), 5.00 (m, 2H), 5.81 (m, 1H).

(4S)-4-hydroxy-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-ynal

A mixture of (5S)-9-((tetrahydro-2H-pyran-2-yl)oxy)non-1-en-7-yn-5-ol (38 g, 159.4 mmol), 1,4-dioxane (798 mL), and water (266 mL) was treated with sodium periodate (136 g, 637.8 mmol) and 2,6-lutidine (37.1 mL, 319.0 mmol). The mixture was cooled with an ice-bath and treated with OsO₄ (0.020 g, 0.08 mmol); the ice-bath was removed, and the mixture was stirred at room temperature (rt) for 20 min. Additional OsO₄ (0.020 g, 0.08 mmol) was added, and stirring was continued at rt for another 6 h. The mixture was diluted with water (1824 mL) and CH₂Cl₂ (836 mL). The organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (836 mL). The organic layers were combined, dried over MgSO₄, and concentrated in vacuo to give the title compound (55 g, 144%).

(4S)-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-yne-1,4-diol

A solution of (4S)-4-hydroxy-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-ynal (55 g, 160 mmol) in methanol (308 mL) was cooled to 0° C. and treated with sodium borohydride (1.818 g, 48.066 mmol), which was added portion wise. After stirring at 0° C. for 1 h, additional sodium borohydride (0.606 g, 16.0 mmol) was added in two portions with a 0.5 h interval, and stirring was continued at 0° C. for another 0.5 h. The reaction was quenched with saturated aqueous NH₄Cl (308 mL) and stirred at room temperature (rt) for 0.5 h. The mixture was extracted sequentially with MTBE (308 mL×2) and ethyl acetate (308 mL×2). The organic layers were combined and washed with brine (116 mL). After concentration, the residue was loaded on silica gel pad and eluted with MTBE (ca. 600 mL). The filtrate was concentrated in vacuo to give the title compound (33.66 g, 87%). ¹H NMR (400 MHz, CDCl₃) δ 1.48-1.86 (m, 10H), 2.34-2.50 (m, 2H), 3.51 (m, 1H), 3.60-3.72 (m, 2H), 3.72-3.88 (m, 2H), 4.25 (m, 2H), 4.80 (m, 1H).

(4S)-4-hydroxy-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-yn-1-yl pivalate

A solution of (4S)-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-yne-1,4-dial (15.0 g, 61.9 mmol) in CH₂Cl₂ (120 mL) was treated with 2,4,6-collidine (34.4 mL, 260 mmol) and cooled to 0° C. After addition of pivaloyl chloride (8.38 mL, 68.094 mmol) and DMAP (0.378 g, 3.095 mmol), the mixture was stirred at 0° C. for 4.5 h. The reaction was quenched with water (105 mL) and extracted twice with MTBE (105 mL). The organic layers were combined, washed with 1 N HCl (105 mL) and brine (45.0 mL), and concentrated in vacuo to give the title compound (22 g, 109%). ¹H NMR (400 MHz, CDCl₃) δ 1.21 (s, 9H), 1.48-1.86 (m, 10H), 2.30-2.50 (m, 2H), 3.52 (m, 1H), 3.72-3.86 (m, 2H), 4.06 (m, 2H), 4.16-4.32 (m, 2H), 4.79 (m, 1H).

(S)-4,8-dihydroxyoct-6-yn-1-yl pivalate

A solution of (4S)-4-hydroxy-8-((tetrahydro-2H-pyran-2-yl)oxy)oct-6-yn-1-yl pivalate (22 g, 67.4 mmol) in methanol (110 mL) was treated with p-TsOH (0.641 g, 3.37 mmol). After being stirred at rt for 5.5 h, the mixture was treated with saturated aqueous NaHCO₃ (56.6 mL) and concentrated in vacuo. The residue was sequentially extracted with MTBE (154 mL) and ethyl acetate (154 mL×2). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 3/2) to give the title compound (7.2 g, 37% for 5 steps). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.55-1.63 (m, 2H), 1.63-1.83 (m, 2H), 2.35 (m, 1H), 2.47 (m, 1H), 3.77 (m, 1H), 4.08 (t, 2H), 4.25 (m, 2H).

(S)-4-hydroxy-8-((mesitylsulfonyl)oxy)oct-6-yn-1-yl pivalate

A 0° C., a mixture of (S)-4,8-dihydroxyoct-6-yn-1-yl pivalate (6.67 g, 27.527 mmol), benzyltriethylammonium chloride (0.313 g, 1.38 mmol), toluene (66.7 mL), and 15% aqueous NaOH (66.7 mL, 250 mmol) was treated with 2-mesitylenesulfonyl chloride (MtsCl) (3.61 g, 16.5 mmol) in toluene (40.0 mL) over 20 min, while maintaining the internal temperature below 5° C. The mixture was stirred at 0° C. for another 1 h. The organic layer was separated, and the aqueous layer was extracted with MTBE (74.1 mL). The organic layers were combined and dried over MgSO₄. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 5/3) to give the title compound (2.49 g, 21%). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.45-1.55 (m, 2H), 1.55-1.83 (m, 4H), 2.30 (s, 3H), 2.62 (s, 6H), 3.65 (m, 1H), 4.08 (t, 2H), 4.69 (m, 2H), 6.99 (s, 2H).

(S)-4-hydroxy-6-methylocta-6,7-dien-1-yl pivalate

A suspension of copper(I) cyanide (0.788 g, 8.80 mmol) in THF (21.4 mL) was cooled to −78° C. and treated with 1.6 M MeLi in diethyl ether (5.50 mL, 8.80 mmol) over 20 min, while maintaining the internal temperature below −60° C. The mixture was stirred −78° C. for 20 min and warmed to 0° C. over 40 min. The mixture was cooled to −78° C., stirred for another 10 min, and treated with a solution of (S)-4-hydroxy-8-((mesitylsulfonyl)oxy)oct-6-yn-1-yl pivalate (2.49 g, 5.87 mmol) in THF (10.7 mL) over 20 min, while maintaining the internal temperature below −65° C. After stirring at −78° C. for 1 h, the reaction was quenched with a mixture of saturated aqueous NH₄Cl (37.4 mL) and 28% aqueous NH₄OH (4.98 mL), and warmed to room temperature (rt). The organic layer was separated, and the aqueous layer was extracted twice with MTBE (24.90 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/3) to give the title compound (1.136 g, 81%). ¹H NMR (400 MHz, CDCl₃) δ 1.28 (s, 9H), 1.48-1.56 (m, 2H), 1.65-1.75 (m, 3H), 1.75-1.85 (m, 2H), 2.00-2.13 (m, 2H), 3.78 (m, 1H), 4.08 (m, 2H), 4.68 (m, 2H).

(S)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-yl acetate

A solution of (S)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-ol (6.0 g, 13.408 mmol) in CH₂Cl₂ (48.0 mL) was treated with triethylamine (3.74 mL, 26.8 mmol), acetic anhydride (1.52 mL, 16.1 mmol), and DMAP (0.164 g, 1.34 mmol). After stirring at room temperature (rt) for 20 h, the reaction was quenched with water (30.0 mL) and diluted with MTBE (30.0 mL). The organic layer was separated and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/20 to 1/8) to give the title compound (5.254 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ 1.05 (s, 9H), 1.52-1.70 (m, 3H), 1.76 (m, 1H), 2.02 (s, 3H), 2.60 (dd, 1H), 2.73 (dd, 1H), 3.68 (m, 2H), 5.19 (m, 1H), 5.49 (s, 1H), 5.63 (s, 1H), 7.39 (m, 6H), 7.65 (m, 4H).

(S)-8-((tert-butyldiphenylsilyl)oxy)-5-hydroxy-3-methyleneoctan-2-one

A solution of (S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide (2.44 g, 8.23 mmol) in a degassed THF (26.0 mL) was treated with chromium(II) chloride (1.01 g, 8.23 mmol), purged with nitrogen for 5 min, and heated to 30° C. After addition of triethylamine (1.15 mL, 8.23 mmol), the mixture was stirred at 30-35° C. for 1 h. The mixture was cooled to 0° C., treated with nickel(II) chloride 2,9-dimethyl-1,10-phenanthroline complex (0.090 g, 0.27 mmol), purged with nitrogen for 5 min, and then treated with a solution of (S)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-yl acetate (1.3 g, 2.7 mmol) in THF (10 mL) (8 mL+2 mL rinse). The mixture was stirred at 0° C. for 10 min and at rt for 2 h. The reaction mixture was treated with Florisil® (5.8 g) and stirred at rt for 30 min. The mixture was diluted with n-heptane (19.5 mL), filtered through florisil pad and rinsed with MTBE (19.5 mL). The filtrate was washed with water (13 mL) and brine (6.50 mL). After concentration, the residue was purified by column chromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give the title compound (613 mg, 56%). ¹H NMR (400 MHz, CDCl₃) δ 1.01 (s, 9H), 1.42-1.70 (m, 4H), 2.32 (dd, 1H), 2.36 (s, 3H), 2.55 (m, 1H), 3.69 (m, 3H), 5.90 (s, 1H), 6.11 (s, 1H), 7.39 (m, 6H), 7.65 (m, 4H).

(S)-5-((tert-butyldimethylsilyl)oxy)-8-((tert-butyldiphenylsilyl)oxy)-3-methyleneoctan-2-one

A solution of (S)-8-((tert-butyldiphenylsilyl)oxy)-5-hydroxy-3-methyleneoctan-2-one (0.643 g, 1.57 mmol) in DMF (5.14 mL) was treated with TBSCl (0.283 g, 1.88 mmol) and imidazole (0.213 g, 3.13 mmol). The mixture was stirred at rt for 4.5 h. The reaction was quenched with water (12.86 mL) and extracted twice with MTBE (19.29 mL). The organic layers were combined, and washed with water (12.9 mL) and brine (6.43 mL). After concentration, the residue was purified by column chromatography (ethyl acetate/n-heptane=1/10 to 1/8) to give the title compound (456 mg, 56%). ¹H NMR (400 MHz, CDCl₃) δ 0.00 (s, 6H), 0.88 (s, 9H), 1.03 (s, 9H), 1.42-1.70 (m, 4H), 2.31 (s, 3H), 2.32 (dd, 1H), 2.44 (dd, 1H), 3.63 (t, 2H), 3.79 (m, 1H), 5.81 (s, 1H), 6.04 (s, 1H), 7.39 (m, 6H), 7.66 (m, 4H).

(S)-2,2,3,3,11,11-hexamethyl-5-(2-methylbuta-2,3-dien-1-yl)-10,10-diphenyl-4,9-dioxa-3,10-disiladodecane

A solution of (S)-5-((tert-butyldimethylsilyl)oxy)-8-((tert-butyldiphenylsilyl)oxy)-3-methyleneoctan-2-one (0.20 g, 0.381 mmol) in ethanol (2.0 mL) was treated with p-toluenesulfonyl hydrazide (0.078 g, 0.42 mmol) and stirred at rt for 59 h. The resulting mixture was treated with ethanol (2.000 mL), triethylamine (0.11 mL, 0.76 mmol), and molecular sieves 4 Å (500 mg). After being stirred at 85° C. (bath) for 1 d, the mixture was filtered through Celite® pad to remove molecular sieves and rinsed with MTBE (20.0 mL). The filtrate was washed with water (5 mL) and brine (5 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/20 to 1/10) to give the title compound (68 mg, 35%). ¹H NMR (400 MHz, CDCl₃) δ 0.01 (s, 3H), 0.02 (s, 3H), 0.87 (s, 9H), 1.04 (s, 9H), 1.42-1.66 (m, 4H), 1.68 (t, 3H), 2.00-2.20 (m, 2H), 3.63 (t, 2H), 3.79 (m, 1H), 4.52 (m, 2H), 7.39 (m, 6H), 7.66 (m, 4H).

Example 7 Preparation of a Compound of Formula (VIIC)

(S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)propane-1,2-diol

A solution of 2-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)acetaldehyde (20.0 g, 33.28 mmol) in methanol (100 mL) was treated with CSA (0.773 g, 3.33 mmol) and stirred at rt for 3 d. The reaction was quenched with saturated aqueous NaHCO₃ (50 mL) and extracted with MTBE (100 mL) and ethyl acetate (100 mL×3). The organic layers were combined, dried over MgSO₄, and concentrated in vacuo to give the title compound (19.79 g). ¹H NMR (400 MHz, CDCl₃) δ 1.80 (m, 1H), 1.85-2.00 (m, 3H), 2.56 (m, 1H), 3.12 (m, 2H), 3.28 (s, 3H), 3.31 (s, 3H), 3.42 (s, 3H), 3.55 (m, 1H), 3.62-3.71 (m, 2H), 3.90-3.98 (m, 3H), 4.43 (m, 1H), 7.60 (m, 2H), 7.69 (m, 1H), 7.98 (m, 2H).

(S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate

A solution of (S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)propane-1,2-diol (19.79 g, 47.29 mmol) in pyridine (99 mL, 1223.429 mmol) was cooled to 0° C. and treated with benzoyl chloride (12.08 mL, 104.0 mmol). The mixture was stirred at rt for 20 h. Additional reagents were added and stirring was continued for 3 d. The reaction was quenched with water (400 mL) and extracted with MTBE (200 mL×3). The organic layers were combined, washed with 1 N HCl (100 mL) and then with saturated aqueous NaHCO₃ (50 mL), dried over MgSO₄, and concentrated in vacuo.

The residue was dissolved in CH₂Cl₂ (297 mL) and treated with triethylamine (26.4 mL, 189.2 mmol), benzoyl chloride (10.98 mL, 94.58 mmol), and DMAP (0.289 g, 2.364 mmol). The mixture was stirred at rt for 24 h. More triethylamine (23.2 mL, 166.3 mmol), benzoyl chloride (7.74 mL, 66.6 mmol), and DMAP (0.578 g, 4.72 mmol) were added and stirring was continued at rt for 7 d. The reaction was quenched with water (300 mL). The organic layer was separated, and the aqueous layer was extracted with CH₂Cl₂ (150 mL). The organic layers were combined and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/1) to give the title compound (17.82 g, 85% for two steps). ¹H NMR (400 MHz, CDCl₃) δ 1.89 (m, 2H), 2.25 (m, 2H), 2.55 (m, 1H), 3.09 (m, 2H), 3.22 (s, 3H), 3.24 (s, 3H), 3.42 (s, 3H), 3.59 (m, 1H), 3.89 (m, 1H), 3.92 (m, 1H), 4.39 (m, 1H), 4.57 (d, 2H), 5.63 (m, 1H), 7.44 (m, 4H), 7.56 (m, 4H), 7.68 (m, 1H), 7.92 (d, 2H), 8.04 (m, 4H).

(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-(2-methoxyacetoxy)-4-methyl-3-methylene-6-(3-(pivaloyloxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenyl sulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate

A mixture of (S)-4-hydroxy-6-methylocta-6,7-dien-1-yl pivalate (1.14 g, 4.73 mmol) and (S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)propane-1,2-diyldibenzoate (3.41 g, 5.44 mmol) was dissolved in CH₂Cl₂ (47.7 mL) and cooled to −40° C. The mixture was sequentially treated with methoxyacetic acid (5.44 mL, 70.9 mmol) and BF₃—OEt₂ (1.80 mL, 14.2 mmol). The mixture was warmed to −30° C. over 1 h and stirred at −30° C. for 0.5 h. The reaction was quenched with saturated aqueous NaHCO₃ (119 mL) and extracted twice with ethyl acetate (100 mL). The organic layers were combined, dried over MgSO₄, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 2/3) to give the title compound (3.61 g, 86%). ¹H NMR (400 MHz, CDCl₃) δ 1.14 (m, 1H), 1.24 (s, 9H), 1.40-1.55 (m, 3H), 1.65 (m, 1H), 1.72 (s, 3H), 1.81 (m, 1H), 1.95 (m, 2H), 2.25 (m, 2H), 2.71 (m, 1H), 3.02 (dd, 1H), 3.11 (dd, 1H), 3.38 (m, 1H), 3.42 (s, 6H), 3.63 (m, 1H), 3.70 (m, 1H), 3.90-4.00 (m, 3H), 4.02 (d, 2H), 4.15 (m, 1H), 4.54 (d, 2H), 4.59 (d, 1H), 4.72 (d, 1H), 5.59 (m, 1H), 7.42 (m, 4H), 7.56 (m, 4H), 7.65 (m, 1H), 7.90 (d, 2H), 8.01 (m, 4H).

(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-(pivaloyloxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate

A mixture of Pd(Ph₃P)₄ (0.467 g, 0.404 mmol) and triphenylphosphine (0.424 g, 1.62 mmol) in a degassed THF (36.1 mL) was heated to 60° C. and stirred for 5 min. The mixture was treated with a mixture of (S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-(2-methoxyacetoxy)-4-methyl-3-methylene-6-(3-(pivaloyloxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenyl sulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyldibenzoate (3.61 g, 4.04 mmol), formic acid (0.775 mL, 20.2 mmol), and triethylamine (2.82 mL, 20.2 mmol) in a degassed THF (36.1 mL). The mixture was stirred at 60° C. for 52 h. After cooling to rt, the mixture was diluted with MTBE (36.1 mL) and washed with water (18.1 mL) and then with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give the title compound (2.8 g, 74% for 2 steps from allene). ¹H NMR (400 MHz, CDCl₃) δ 1.00 (m, 1H), 1.05 (d, 3H), 1.14 (s, 9H), 1.38 (m, 3H), 1.61 (m, 1H), 1.72 (m, 1H), 1.91 (m, 1H), 2.1-2.32 (m, 4H), 2.62 (m, 1H), 3.02 (dd, 1H), 3.06 (dd, 1H), 3.36 (m, 1H), 3.42 (s, 3H), 3.66 (m, 1H), 3.72 (m, 1H), 3.81 (m, 1H), 3.84-3.96 (m, 3H), 4.56 (d, 2H), 4.77 (s, 1H), 4.83 (s, 1H), 5.59 (m, 1H), 7.40 (m, 4H), 7.52 (m, 4H), 7.62 (m, 1H), 7.90 (m, 2H), 8.01 (m, 4H).

3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propyl pivalate

A solution of (S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-(pivaloyloxy) propyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate (2.8 g, 3.5 mmol) in a mixture of THF (2.80 mL) and methanol (56.0 mL) was treated with 6-10% Mg(OMe)₂ in methanol (18.5 g, 13.9 mmol). After stirring at rt for 22 h, the reaction was quenched with saturated aqueous NH₄Cl (22.4 mL) and extracted with MTBE (56.0 mL) and ethyl acetate (42.0 mL×2). The organic layers were combined and dried over MgSO₄. After concentration, the residue was azeotroped with methanol and toluene to give a crude product, which was used for the next step without further purification. ¹H NMR (400 MHz, CDCl₃) δ 1.02 (m, 1H), 1.05 (d, 3H), 1.30 (s, 9H), 1.38 (m, 3H), 1.61 (m, 1H), 1.72 (m, 1H), 1.85 (m, 1H), 1.90-2.03 (m, 2H), 2.05-2.27 (m, 2H), 2.67 (m, 1H), 3.05 (bd, 1H), 3.23 (dd, 1H), 3.42 (s, 3H), 3.45 (m, 1H), 3.60 (m, 1H), 3.70 (m, 1H), 3.75 (m, 1H), 3.80-4.01 (m, 5H), 4.10 (m, 1H), 4.80 (s, 1H), 4.88 (s, 1H), 7.60 (m, 2H), 7.62 (m, 1H), 7.95 (m, 2H).

3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propyl pivalate

A solution of 3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propyl pivalate (2.07 g, 3.469 mmol) in DMF (16.56 mL, 213.871 mmol) was treated with imidazole (0.945 g, 13.9 mmol) and TBSCl (1.20 g, 7.98 mmol). The mixture was stirred at rt for 1 h. Additional imidazole (0.945 g, 13.9 mmol) and TBSCl (1.20 g, 7.98 mmol) were added, and stirring was continued at rt for another 18 h. The reaction was quenched with water (41.4 mL) and extracted with MTBE (41.4 mL×2). The organic layers were combined and dried over MgSO₄. After concentration, the residue was purified by silica gel column chromatography (1/10 to 1/5) to give the title compound (3.115 g, 109%). ¹H NMR (400 MHz, CDCl₃) δ 0.03 (s, 6H), 0.09 (s, 6H), 0.91 (s, 18H), 1.02 (m, 1H), 1.05 (d, 3H), 1.15 (s, 9H), 1.40 (m, 3H), 1.61 (m, 1H), 1.72 (m, 1H), 1.82 (m, 1H), 1.90 (m, 1H), 1.99 (m, 1H), 2.15-2.27 (m, 2H), 2.58 (m, 1H), 3.02 (m, 2H), 3.39 (m, 1H), 3.40 (s, 3H), 3.45 (m, 1H), 3.55 (m, 1H), 3.65 (m, 2H), 3.75-3.85 (m, 3H), 3.85-4.0 (m, 2H), 4.79 (s, 1H), 4.88 (s, 1H), 7.60 (m, 2H), 7.62 (m, 1H), 7.92 (m, 2H).

3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propan-1-ol

A solution of 3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propyl pivalate (3.11 g, 3.77 mmol) in CH₂Cl₂ (31.1 mL) was cooled to −78° C. and treated with 1M DIBAL in toluene (8.29 mL, 8.29 mmol). The mixture was stirred at −78° C. for 1 h. Additional 1M DIBAL in toluene (1.507 mL, 1.507 mmol) was added, and stirring was continued for another 1.5 h. After quenching the reaction with methanol (1.53 mL, 37.7 mmol), the mixture was treated with 1 N HCl (37.7 mL) and stirred at rt for 1 h. The mixture was extracted with MTBE (31.1 mL×2). The organic layers were combined, washed with saturated aqueous NaHCO₃ (15.6 mL), dried over MgSO₄, and concentrated in vacuo to give the title compound (2.9 g, 104%). ¹H NMR (400 MHz, CDCl₃) δ 0.03 (s, 6H), 0.09 (s, 6H), 0.88 (s, 18H), 1.08 (m, 1H), 1.08 (d, 3H), 1.48 (m, 3H), 1.63 (m, 1H), 1.72 (m, 1H), 1.82 (m, 1H), 1.88-2.02 (m, 2H), 2.12-2.27 (m, 2H), 2.58 (m, 1H), 3.03 (dd, 1H), 3.10 (dd, 1H), 3.40 (s, 3H), 3.42-3.50 (m, 2H), 3.55 (m, 3H), 3.68 (m, 2H), 3.80 (m, 3H), 4.79 (s, 1H), 4.88 (s, 1H), 7.60 (m, 2H), 7.62 (m, 1H), 7.97 (m, 2H).

(S)-5-(((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl) methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane

A solution of 3-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy) propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)propan-1-ol (2.9 g, 3.9 mmol) in CH₂Cl₂ (29.0 mL) was treated with triethylamine (1.09 mL, 7.83 mmol) and chlorotriethylsilane (0.799 mL, 4.70 mmol). After stirring at rt for 17 h, the reaction was quenched with water (29.0 mL) and extracted twice with MTBE (29.0 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/20 to 1/5) to give the title compound (2.95 g, 88%). ¹H NMR (400 MHz, CDCl₃) δ 0.03 (s, 6H), 0.04 (s, 6H), 0.56 (q, 6H), 0.82-1.00 (m, 27H), 1.02 (m, 1H), 1.06 (d, 3H), 1.30-1.52 (m, 4H), 1.74 (m, 1H), 1.78-1.90 (m, 2H), 2.00 (m, 1H), 2.15-2.23 (m, 2H), 2.56 (m, 1H), 2.96-3.10 (m, 2H), 3.35 (m, 1H), 3.43 (s, 3H), 3.43-3.62 (m, 5H), 3.68 (m, 1H), 3.79 (m, 2H), 3.83 (m, 1H), 4.78 (s, 1H), 4.85 (s, 1H), 7.60 (m, 2H), 7.62 (m, 1H), 7.96 (m, 2H).

Example 7 Preparation of a Compound of Formula (VD)

(R)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-yl benzoate

A solution of (S)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-ol (25.0 g, 55.9 mmol) in toluene (200 mL) was treated with benzoic acid (8.19 g, 67.0 mmol) and triphenylphosphine (17.58 g, 67.0 mmol). After cooling to 0° C., the mixture was treated with DEAD (24.32 mL, 61.46 mmol) over 20 min, while maintaining the internal temperature below 6° C. and stirred at 0° C. for 2 h. The mixture was treated with n-heptane (83 mL) and stirred at 0° C. for 30 min. The precipitate was filtered and washed with n-heptane (83 mL). The filtrate was concentrate in vacuo to give the title compound (46.6 g).

(R)-2-bromo-7-hydroxyhept-1-en-4-yl benzoate

A solution of (R)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-yl benzoate (30.8 g, 55.8 mmol) in acetonitrile (200 mL) was treated with 48% HF in water (10.1 mL, 279 mmol) and stirred at rt for 13 h. The reaction was quenched with saturated aqueous NaHCO₃ (308 mL) and diluted with MTBE (154 mL). The organic layer was separated, and the aqueous layer was extracted with MTBE (154 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give the title compound (14.67 g, 84%). ¹H NMR (400 MHz, CDCl₃) δ 1.29 (m, 1H), 1.61-1.71 (m, 2H), 1.75-1.90 (m, 2H), 2.73 (dd, 1H), 2.90 (dd, 1H), 3.69 (t, 2H), 5.46 (m, 1H), 5.48 (s, 1H), 5.69 (s, 1H), 7.41 (m, 2H), 7.58 (m, 1H), 8.02 (m, 2H).

(R)-2-bromo-7-oxohept-1-en-4-yl benzoate

A solution of 2 M oxalyl chloride in CH₂Cl₂ (6.96 mL, 13.9 mmol) in CH₂Cl₂ (21.80 mL) was cooled to −78° C. and treated with DMSO (1.976 mL, 27.843 mmol), while maintaining the internal temperature below −60° C. After stirring at −78° C. for 10 min, a solution of (R)-2-bromo-7-hydroxyhept-1-en-4-yl benzoate (2.18 g, 6.961 mmol) in CH₂Cl₂ (10.90 mL) was added, and stirring was continued at −78° C. for 30 min. Triethylamine (9.70 mL, 69.6 mmol) was added, while maintaining the internal temperature below −60° C. Then, the mixture was stirred at −78° C. for 10 min and 0° C. for 30 min. The mixture was treated with water (21.80 mL) and extracted twice with MTBE (32.7 mL). The organic layers were combined, and washed with water (21.80 mL) and brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/3) to give the title compound (1.477 g, 68%).

¹H NMR (400 MHz, CDCl₃) δ 2.04 (m, 1H), 2.14 (m, 1H), 2.60 (m, 2H), 2.73 (dd, 1H), 2.92 (dd, 1H), 5.45 (m, 1H), 5.50 (s, 1H), 5.70 (s, 1H), 7.43 (m, 2H), 7.58 (m, 1H), 8.02 (m, 2H), 9.79 (s, 1H).

2-((2R,4aS,6S,7R,8S,8aS)-7,8-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)ethanol

Methyl 2-((2R,4aS,6S,7R,8S,8aS)-7,8-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)acetate (90.0 g, 31.5 mmol, a solution in toluene, ca. 27%) was diluted with toluene (316 mL) and cooled to −78° C. The mixture was treated with 1M DIBAL in toluene (37.8 mL, 37.8 mmol) and stirred at −78° C. for 1 h. After removing the cold bath, the reaction was quenched with methanol (7.65 mL, 189 mmol) and treated with 1 N HCl (243 mL, 243 mmol) and MTBE (170 mL). After stirring at rt for 30 min, the organic layer was separated, and the aqueous layer was extracted with MTBE (170 mL). The organic layers were combined, washed sequentially with 1 N HCl (122 mL), water (122 mL), saturated aqueous NaHCO₃ (122 mL), and brine (120 mL).

After concentration, the residue was dissolved in methanol (194 mL), cooled to 0° C., and treated with sodium borohydride (0.596 g, 15.8 mmol). The reaction mixture was stirred at 0° C. for 1 h and quenched with 1 N HCl (63.0 mL, 63.0 mmol). After dilution with MTBE (365 mL), the organic layer was separated and washed sequentially with 1 N HCl (63.0 mL) and saturated aqueous NaHCO₃ (122 mL) (with brine). The organic layer was dried over MgSO₄ and concentrated in vacuo to give the title compound (23.44 g, 100%).

((2S,3R,4S,4aS,6R,8aS)-2-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3,4-diyl)bis(oxy))bis(tert-butyldimethylsilane

A solution of 2-((2R,4aS,6S,7R,8S,8aS)-7,8-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl) octahydropyrano[3,2-b]pyran-2-yl)ethanol (23.44 g, 31.548 mmol) in CH₂Cl₂ (211 mL) was treated with chlorotriethylsilane (6.44 mL, 37.9 mmol) and triethylamine (8.79 mL, 63.1 mmol), and stirred at rt for 3 h. Additional chlorotriethylsilane (1.06 mL, 6.31 mmol) and triethylamine (1.32 mL, 9.46 mmol) were added, and stirring was continued at rt for another 8 h. The reaction was quenched with water (117 mL). The organic layer was separated, and the aqueous layer was extracted with MTBE (117 mL). The organic layers were combined, and dried over MgSO₄. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/20 to 1/10) to give the title compound (23.7 g, 95%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (s, 3H), 0.03 (s, 3H), 0.10 (s, 3H), 0.11 (s, 3H), 0.12 (s, 3H), 0.14 (s, 3H), 0.59 (q, 6H), 0.86 (s, 9H), 0.9-1.0 (m, 27H), 1.25-1.35 (m, 2H), 1.60-1.72 (m, 3H), 1.92 (m, 1H), 2.84 (d, 1H), 3.45 (m, 2H), 3.58 (m, 1H), 3.73 (m, 1H), 3.83 (dd, 1H), 3.89 (dd, 1H), 4.09 (m, 1H), 4.91 (m, 1H), 6.29 (d, 1H), 6.85 (dd, 1H).

(4R,10S,E)-10-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-2-bromo-10-((tert-butyldimethylsilyl)oxy)-7-hydroxydeca-1,8-dien-4-yl benzoate

A solution of (((2S,3R,4S,4aS,6R,8aS)-2-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3,4-diyl)bis(oxy))bis(tert-butyldimethylsilane) (4.48 g, 5.22 mmol) in THF (32.5 mL) was cooled to −78° C. and treated with 1.6 M n-BuLi in n-hexane (3.26 mL, 5.22 mmol), while maintaining the internal temperature below −65° C. After stirring at −78° C. for 20 min, the mixture was treated with a solution of magnesium bromide diethyl etherate (1.35 g, 5.22 mmol) in THF (16.25 mL), while maintaining the internal temperature below −65° C., and stirred at −78° C. for 30 min. A solution of (R)-2-bromo-7-oxohept-1-en-4-yl benzoate (1.477 g, 4.747 mmol) and magnesium bromide diethyl etherate (1.35 g, 5.22 mmol) in THF (18.3 mL) was added, and the resulting mixture was stirred at −78° C. for 10 min, slowly warmed to −25° C. over 4 h and stirred at −25° C. for 1 h. The reaction was quenched with saturated aqueous NH₄Cl (29.5 mL) and extracted twice with MTBE (29.5 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/5) to give the title compound (3.35 g, 68%).

(4R,10S,E)-10-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-2-bromo-10-((tert-butyldimethylsilyl)oxy)-7-oxodeca-1,8-dien-4-yl benzoate

A solution of (4R,10S,E)-10-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy) ethyl)octahydropyrano[3,2-b]pyran-2-yl)-2-bromo-10-((tert-butyldimethylsilyl)oxy)-7-hydroxydeca-1,8-dien-4-yl benzoate (3.35 g, 3.213 mmol) in CH₂Cl₂ (33.5 mL) was treated with sodium bicarbonate (0.540 g, 6.43 mmol) and Dess-Martin periodinane (1.64 g, 3.86 mmol). The mixture was stirred at rt for 1 h. The reaction was quenched with saturated aqueous NaHCO₃ (25.1 mL) and 20% Na₂SO₃ (25.1 mL) and extracted twice with MTBE (26.8 mL). The organic layers were combined and washed with brine (16.75 mL). After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/20 to 1/8) to give the title compound (2.26 g, 68%). ¹H NMR (400 MHz, CDCl₃) δ 0.07 (s, 3H), 0.02 (s, 3H), 0.11 (s, 6H), 0.12 (s, 3H), 0.13 (s, 3H), 0.60 (q, 6H), 0.82 (s, 9H), 0.88 (t, 9H), 0.92 (s, 9H), 0.94 (s, 9H), 1.05-1.25 (m, 3H), 1.48-1.60 (m, 3H), 1.70 (m, 1H), 2.00-2.20 (m, 2H), 2.69 (m, 2H), 2.72 (dd, 1H), 2.82 (d, 2H), 2.91 (dd, 1H), 3.29 (m, 1H), 3.42 (m, 1H), 3.63 (m, 1H), 3.72 (m, 1H), 3.91 (m, 2H), 4.10 (bs, 1H), 5.11 (m, 1H), 5.43 (m, 1H), 5.49 (d, 1H), 5.68 (s, 1H), 6.29 (d, 1H), 7.08 (dd, 1H), 7.41 (m, 2H), 7.52 (m, 1H), 8.01 (m, 2H).

(R)-2-bromo-8-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-3,9-dihydroxy-7-(2-hydroxyethyl) decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)-7-oxooct-1-en-4-yl benzoate

A mixture of imidazole hydrochloride (0.704 g, 6.73 mmol) and 1 M TBAF in THF (14.12 mL, 14.1 mmol) in THF (45.2 mL) was treated with a solution of (4R,10S,E)-10-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl) octahydropyrano[3,2-b]pyran-2-yl)-2-bromo-10-((tert-butyldimethylsilyl)oxy)-7-oxodeca-1,8-dien-4-yl benzoate (2.26 g, 2.17 mmol) in THF (31.6 mL). The mixture was stirred at rt for 7 d. The mixture was treated with toluene (56.5 mL) and water (56.5 mL). The organic layer was separated, and the aqueous layer was extracted twice with a mixture of toluene (38.4 mL) and THF (38.4 mL). The organic layers were combined, concentrated in vacuo and then azeotroped three times with acetonitrile (18.1 mL) to give the title compound (1.4 g).

(R)-5-bromo-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(2-hydroxyethyl) dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)hex-5-en-3-yl benzoate

A solution of (R)-2-bromo-8-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-3,9-dihydroxy-7-(2-hydroxyethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)-7-oxooct-1-en-4-yl benzoate (1.27 g, 2.17 mmol) in CH₂Cl₂ (68.4 mL) was treated with PPTS (3.00 g, 11.9 mmol) and stirred at rt for 23 h. After concentration, the residual solid (PPTS) was treated with ethyl acetate (50.7 mL), stirred at rt for 10 min, filtered, and rinsed with ethyl acetate. The filtrate was concentrated, treated again with ethyl acetate (10.14 mL), and stirred at rt for 2 h. The precipitate was filtered, washed with ethyl acetate (3 mL), and dried under N₂ purge to give the title compound (1^(st) crop, 495 mg, contaminated with 14% PPTS).

The filtrate was treated with ethyl acetate (ca. 3 mL) at 40° C. and stirred at ambient temperature for 2 h. The precipitate was filtered, washed with ethyl acetate (1 mL), and dried under N₂ purge to give the title compound (2^(nd) crop, 175 mg, total 47% (1^(st) and 2^(nd) crops combined) for 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 1.30-1.50 (m, 2H), 1.65-2.16 (m, 10H), 2.79 (m, 1H), 2.86-2.94 (m, 2H), 3.61 (m, 1H), 3.70-3.84 (m, 2H), 4.05 (dd, 1H), 4.19 (dd, 1H), 4.27 (m, 1H), 4.42 (m, 1H), 4.60 (dd, 1H), 4.68 (dd, 1H), 5.40 (m, 1H), 5.47 (s, 1H), 5.68 (s, 1H), 7.41 (m, 2H), 7.57 (m, 1H), 8.03 (m, 2H).

(R)-5-bromo-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(2-oxoethyl)decahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2(3H)-yl)hex-5-en-3-yl benzoate

A mixture of (R)-5-bromo-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(2-hydroxyethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)hex-5-en-3-yl benzoate (0.49 g, 0.87 mmol) and sodium bicarbonate (0.182 g, 2.17 mmol) in CH₂Cl₂ (4.9 mL) was treated with Dess-Martin periodinane (0.551 g, 1.30 mmol), and stirred at rt for 2 h. The reaction was quenched with 20% Na₂SO₃ (2.5 mL) and saturated aqueous NaHCO₃ (2.5 mL). The mixture was extracted three times with MTBE (4.9 mL) and ethyl acetate (4.9 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo.

The residue was dissolved in ethyl acetate (ca. 3 mL) with heating and slowly cooled to rt over 20 h. The precipitate was filtered, washed with ethyl acetate (1 mL), and dried under N₂ purge for 2 h to give the title compound (216 mg, 44%) along with 200 mg from the filtrate. ¹H NMR (400 MHz, CDCl₃) δ 1.40 (m, 2H), 1.77 (m, 1H), 1.86 (m, 1H), 1.92-2.16 (m, 6H), 2.48 (m, 1H), 2.73 (m, 1H), 2.78 (m, 1H), 2.87-2.95 (m, 2H), 3.89 (m, 1H), 4.08 (dd, 1H), 4.20 (dd, 1H), 4.28 (m, 1H), 4.43 (m, 1H), 4.51 (dd, 1H), 4.69 (dd, 1H), 5.46 (m, 1H), 5.48 (s, 1H), 5.68 (s, 1H), 7.43 (m, 2H), 7.55 (m, 1H), 8.03 (m, 2H), 9.79 (s, 1H).

(3R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert- butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl) tetrahydrofuran-3-yl)-2-hydroxy-3-(phenylsulfonyl)propyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl benzoate

A solution of (S)-5-(((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (0.478 g, 0.559 mmol) in THF (4.2 mL) was cooled to −5° C. The mixture was treated with 1.6 M n-BuLi in n-hexane (0.349 mL, 0.559 mmol) and stirred at −5° C. for 30 min. After cooling to −78° C., the mixture was treated with a solution of (R)-5-bromo-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(2-oxoethyl) dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)hex-5-en-3-yl benzoate (0.21 g, 0.373 mmol) in a mixture of n-heptane (1.1 mL) and THF (3.2 mL), while maintaining the internal temperature below −65° C. After stirring at −78° C. for 4 h, the reaction was quenched with saturated aqueous NH₄Cl (5 mL) and extracted three times with MTBE (10 mL). The organic layers were combined, dried over MgSO₄ and concentrated in vacuo to give the title compound (690 mg, 130%).

(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert- butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl) tetrahydrofuran-3-yl)-2-oxo-3-(phenylsulfonyl)propyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl benzoate

A solution of (3R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert- butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-hydroxy-3-(phenylsulfonyl)propyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl benzoate (0.69 g, 0.49 mmol) in CH₂Cl₂ (6.9 mL) was treated with sodium bicarbonate (0.061 g, 0.73 mmol) and Dess-Martin periodinane (0.248 g, 0.584 mmol). The reaction mixture was stirred at rt for 1 h, quenched with saturated aqueous NaHCO₃ (6.9 mL) and 20% Na₂SO₃ (6.9 mL), and extracted twice with MTBE (10.35 mL, 86.888 mmol). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give the title compound (366 mg, 69% for 2 steps).

(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert- butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl) tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl benzoate

A solution of (R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert- butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxo-3-(phenylsulfonyl)propyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl benzoate (0.366 g, 0.258 mmol) in a mixture of THF (2.9 mL) and methanol (1.8 mL) was cooled to −78° C. and treated with 0.1M SmI₂ in THF (5.55 mL, 0.555 mmol). After stirring at −78° C. for 1 h, the cold bath was removed, and the mixture was treated with a mixture of potassium sodium tartrate (1.83 g, 6.48 mmol) and potassium carbonate (1.7 g, 13 mmol) in water (18.3 mL). The mixture was vigorously stirred at rt for 10 min and extracted twice with MTBE (7.32 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give the title compound (289 mg, 88%). ¹H NMR (400 MHz, CDCl₃) δ 0.15 (s, 9H), 0.30 (s, 3H), 0.58 (q, 6H), 0.88 (s, 9H), 0.89 (s, 9H), 0.95 (t, 9H), 0.98-1.05 (m, 2H), 1.06 (d, 3H), 1.20-1.72 (m, 7H), 1.72-1.84 (m, 3H), 1.84-2.16 (m, 9H), 2.25 (m, 1H), 2.42 (m, 2H), 2.55 (dd, 1H), 2.72-2.86 (m, 2H), 2.92 (m, 2H), 3.34 (dd, 1H), 3.52 (s, 3H), 3.44-3.68 (m, 6H), 3.75 (m, 2H), 3.85 (m, 2H), 4.04 (m, 1H), 4.19 (dd, 1H), 4.24 (m, 1H), 4.39 (m, 1H), 4.59 (m, 1H), 4.67 (m, 1H), 4.78 (s, 1H), 4.84 (m, 1H), 5.45 (m, 1H), 5.48 (s, 1H), 5.68 (s, 1H), 7.41 (m, 2H), 7.58 (m, 1H), 8.02 (m, 2H).

1-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(3-hydroxypropyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxytetrahydrofuran-3-yl)-3-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-((R)-5-bromo-3-hydroxyhex-5-en-1-yl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one

A solution of (R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert- butyldimethylsilyl)oxy) propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl) tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl benzoate (0.285 g, 0.223 mmol) in a mixture of methanol (5.7 mL) and THF (0.29 mL) was treated with 6-10% Mg(OMe)₂ in methanol (1.29 g, 0.893 mmol) and stirred at rt for 5 d. Potassium carbonate (0.093 g, 0.67 mmol) was added, and stirring was continued at rt for another 1 d. The reaction was quenched with saturated aqueous NH₄Cl (4.28 mL) and brine (4.28 mL) and extracted three times with MTBE (11.40 mL). The organic layers were combined, dried over MgSO₄, and concentrated in vacuo to give the title compound (280 mg, 119%).

1-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl) methyl)tetrahydrofuran-3-yl)-3-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-((R)-5-bromo-3-hydroxyhex-5-en-1-yl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one

A solution of 1-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-2-(((2R,4R,6S)-6-(3-hydroxypropyl)-4-methyl-3-methylenetetrahydro-2H-pyran-2-yl)methyl)-4-methoxy tetrahydrofuran-3-yl)-3-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-((R)-5-bromo-3-hydroxyhex-5-en-1-yl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one (0.28 g, 0.265 mmol) in CH₂Cl₂ (5.6 mL) was cooled to −78° C. and treated with 2,6-lutidine (0.123 mL, 1.06 mmol) and chlorotriethylsilane (0.054 mL, 0.32 mmol). The reaction mixture was stirred at −78° C. for 2 h. The reaction was quenched with methanol (0.107 mL, 2.65 mmol) and stirred at −78° C. for 10 min. After removing the cold bath, the mixture was treated with water (5.6 mL) and warmed to rt. The mixture was extracted twice with MTBE (11.20 mL). The organic layers were combined, washed with 0.1 N HCl (6.09 mL, 0.609 mmol) and saturated aqueous NaHCO₃ (2.80 mL), dried over MgSO₄, and concentrated in vacuo to give the title compound (327 mg, 105%).

(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert- butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl) tetrahydrofuran-3-yl)-2-oxopropyl)decahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2(3H)-yl)-5-bromohex-5-en-3-yl 4-methylbenzenesulfonate

1-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl) methyl)tetrahydrofuran-3-yl)-3-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-((R)-5-bromo-3-hydroxyhex-5-en-1-yl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)propan-2-one (0.327 g, 0.279 mmol) was dissolved in CH₂Cl₂ (4.9 mL) and treated with DMAP (0.102 g, 0.837 mmol) and p-TsCl (0.064 g, 0.34 mmol). The mixture was stirred at rt for 16 h. Additional DMAP (0.020 g, 0.17 mmol) and p-TsCl (0.016 g, 0.084 mmol) were added, and stirring was continued at rt for another 24 h. The reaction mixture was diluted with MTBE (20 mL) and sequentially washed with 0.1 N HCl (8.4 mL×2), saturated aqueous NaHCO₃ (3.3 mL), and brine (3.3 mL). After concentration, the residue was purified by column chromatography (ethyl acetate/n-heptane=1/10 to 2/3) to give the title compound (215 mg, 72% for 3 steps). ¹H NMR (400 MHz, CDCl₃) □0.03 (2s, 9H), 0.60 (s, 3H), 0.59 (q, 6H), 0.85 (s, 9H), 0.87 (s, 9H), 0.94 (t, 9H), 0.96-1.10 (m, 2H), 1.06 (d, 3H), 1.28-1.60 (m, 5H), 1.60-1.84 (m, 6H), 1.84-2.16 (m, 8H), 2.24 (m, 1H), 2.42 (m, 2H), 2.51 (dd, 1H), 2.64 (dd, 1H), 2.72 (dd, 1H), 2.82 (dd, 1H), 2.90 (d, 1H), 3.26 (m, 1H), 3.52 (s, 3H), 3.44-3.68 (m, 6H), 3.75 (m, 2H), 3.84 (m, 2H), 4.04 (m, 1H), 4.19 (m, 1H), 4.35 (m, 1H), 4.58 (m, 1H), 4.66 (m, 1H), 4.67 (m, 1H), 4.78 (s, 1H), 4.85 (m, 1H), 4.84 (s, 1H), 5.35 (m, 1H), 5.58 (s, 1H), 7.35 (d, 2H), 7.80 (d, 2H)

(R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert- butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-oxopropyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl 4-methylbenzenesulfonate

A solution of 2 M oxalic chloride in CH₂Cl₂ (0.810 mL, 1.62 mmol) in CH₂Cl₂ (4.30 mL) was cooled to −78° C. and treated with DMSO (0.230 mL, 3.24 mmol). After stirring for 10 min at −78° C., a solution of (R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl) tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl 4-methylbenzenesulfonate (0.215 g, 0.162 mmol) in CH₂Cl₂ (2.2 mL) was added. The mixture was stirred at −78° C. for 10 min and at −40° C. for 1 h. After cooling back to −78° C., the mixture was treated with triethylamine (1.13 mL, 8.10 mmol) and stirred at −78° C. for 10 min and at 0° C. for 20 min. The resulting mixture was treated with water (4.3 mL) and diluted with MTBE (21.5 mL). The organic layer was separated and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/1) to give the title compound (166 mg, 85%).

BisTBS Ether

Chromous chloride (0.520 g, 4.23 mmol) was added to a 3-necked flask, which was purged with N₂ for 5 min, and to the flask was added a solution of (R)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide (1.25 g, 4.23 mmol) in a degassed THF (7.5 mL). The mixture was heated to 30° C., treated with triethylamine (0.590 mL, 4.23 mmol), and stirred at 33° C. for 1 h. After cooling to 0° C., the mixture was treated with nickel(II) chloride 2,9-dimethyl-1,10-phenanthroline complex (0.023 g, 0.069 mmol) and purged with N₂ for 5 min. After removing the ice-bath, a solution of (R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-oxopropyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl 4-methylbenzenesulfonate (0.083 g, 0.069 mmol) in a degassed THF (4.98 mL) was added over 2 h by syringe pump. The mixture was stirred at rt for another 2 h. After cooling to 0° C., the reaction was quenched with ethylenediamine (0.926 mL, 13.7 mmol), while maintaining the internal temperature below 10° C., and stirred at rt for 10 min. The mixture was treated with water (9.96 mL) and extracted twice with MTBE (9.96 mL). The organic layers were combined, dried over MgSO₄, and concentrated in vacuo.

The residue was dissolved in isopropanol (IPA) (4.98 mL), treated with silica gel (166 mg), and stirred at rt for 23 h. The precipitate was filtered and washed with IPA (3 mL) and heptane (3 mL). The filtrate was aged in a freezer for 2 d. The resulting precipitate was filtered and washed with IPA (5 mL). The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 3/2) to give the title compound (33 mg, 50%), the structure of which was confirmed by comparison of its ¹H NMR spectrum with that of an authentic sample. ¹H NMR (400 MHz, C₆D₆) δ 0.05 (s, 6H), 0.14 (s, 3H), 0.16 (s, 3H), 0.77 (d, 3H), 0.94 (s, 9H), 0.99 (s, 9H), 1.05-1.30 (m, 2H), 1.30-1.46 (m, 3H), 1.20-1.72 (m, 2H), 1.50-1.70 (m, 3H), 1.84-2.00 (m, 4H), 2.05-2.20 (m, 3H), 2.28-2.40 (m, 4H), 2.50 (m, 2H), 2.60 (m, 2H), 2.70 (m, 2H), 2.86 (m, 1H), 3.50 (m, 1H), 3.52-3.72 (m, 4H), 3.58 (s, 3H), 3.74-3.84 (m, 2H), 3.95 (m, 1H), 4.00-4.22 (m, 7H), 4.04 (m, 1H), 4.38 (m, 1H), 4.56 (bm, 1H), 4.57 (s, 1H), 4.74 (s, 1H), 4.98 (m, 2H).

All compounds were prepared following the same procedures shown above starting from (S)-2-bromo-7-((tert-butyldiphenylsilyl)oxy)hept-1-en-4-yl benzoate.

(S)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert- butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-oxopropyl)tetrahydro-2H-pyran-2-yl)methyl)tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl benzoate

The compound was prepared following the same procedures shown above for (3R)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-((triethylsilyl)oxy)propyl)tetrahydro-2H-pyran-2-yl)methyl) tetrahydrofuran-3-yl)-2-hydroxy-3-(phenylsulfonyl)propyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl benzoate with the exception that (S)-5-bromo-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(2-oxoethyl)decahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2(3H)-yl)hex-5-en-3-yl benzoate was used as a starting material.

NHK Macrocyclization

Chromous chloride (0.636 g, 5.18 mmol) was added to a 3-necked flask, which was purged with N₂ for 5 min, and to the flask was added a solution of (S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide (1.535 g, 5.18 mmol) in a degassed THF (6.80 mL). The resulting mixture was heated to 30° C., charged with triethylamine (0.722 mL, 5.18 mmol), and stirred at 33° C. for 1 h. After cooling to 0° C., the mixture was treated with nickel(II) chloride 2,9-dimethyl-1,10-phenanthroline complex (0.040 g, 0.12 mmol) and purged with N₂ for 5 min. After removing the ice-bath, a solution of (S)-1-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-7-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert- butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(((2R,4R,6S)-4-methyl-3-methylene-6-(3-oxopropyl)tetrahydro-2H-pyran-2-yl)methyl) tetrahydrofuran-3-yl)-2-oxopropyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-2-yl)-5-bromohex-5-en-3-yl benzoate (compound 8; 0.136 g, 0.117 mmol) in a degassed THF (6.80 mL) was added over 1.5 h by syringe pump. The mixture was stirred at rt for another 2 h. The reaction was cooled to 0° C., quenched with ethylenediamine (1.045 mL, 15.47 mmol), while maintaining the internal temperature below 10° C., and stirred at rt for 10 min. The mixture was treated with water (16.3 mL) and extracted with n-heptane (8.2 mL) and then twice with MTBE (16.3 mL). The organic layers were combined, dried over MgSO₄, and concentrated in vacuo. The residue was treated with n-heptane (20 mL) and stirred at rt for 20 min. The precipitated ligand was filtered off and rinsed with heptane (20 mL) and IPA (10 mL). The filtrate was aged in a freezer (−20° C.) for 20 h. The precipitate was filtered and rinsed with IPA. The filtrate was concentrated and purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/1) to give compound 16 (88 mg, 69%). ¹H NMR (400 MHz, CDCl₃) δ 0.02 (s, 9H), 0.6 (s, 3H), 0.86 (s, 18H), 1.10 (m, 4H), 1.42 (m, 3H), 1.64-2.00 (m, 8H), 2.06-2.30 (m, 8H), 2.45 (m, 2H), 2.64 (m, 2H), 2.94 (m, 2H), 3.11 (m, 1H), 3.19 (m, 1H), 3.36 (s, 3H), 3.48 (m, 1H), 3.56 (m, 1H), 3.64-3.90 (m, 5H), 3.80-4.30 (m, 4H), 4.41 (m, 1H), 4.59 (m, 1H), 4.68 (m, 1H), 4.79 (m, 1H), 4.92 (s, 1H), 5.06 (s, 1H), 5.28 (s, 1H), 5.40 (m, 1H), 7.41 (m, 2H), 7.58 (m, 1H), 8.02 (m, 2H).

Mesylation of NHK Product

A solution of Compound 16 (0.084 g, 0.078 mmol) in THF (2.94 mL) was cooled to 0° C. and treated with triethylamine (0.043 mL, 0.31 mmol) and methanesulfonyl chloride (0.018 mL, 0.23 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with water (3.36 mL) and extracted three times with MTBE (5.04 mL). The organic layers were combined, dried over MgSO₄, and concentrated to give compound 17 (88 mg).

Cyclization with KOMe

A solution of compound 17 (0.080 g, 0.069 mmol) in THF (4.0 mL) was cooled to 0° C. and treated with 25% potassium methoxide in methanol (0.068 g, 0.24 mmol). The mixture was slowly warmed to rt over 20 h. The reaction was quenched with saturated aqueous NH₄Cl (2.4 mL) and extracted three times with MTBE (6.4 mL). The organic layers were combined and dried over MgSO₄. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 2/1) to give compound 18 (45 mg, 68% for 2 steps). ¹H NMR (400 MHz, C₆D₆) δ 0.05 (s, 6H), 0.14 (s, 3H), 0.16 (s, 3H), 0.77 (d, 3H), 0.94 (s, 9H), 0.99 (s, 9H), 1.05-1.30 (m, 2H), 1.30-1.46 (m, 3H), 1.20-1.72 (m, 2H), 1.50-1.70 (m, 3H), 1.84-2.00 (m, 4H), 2.05-2.20 (m, 3H), 2.28-2.40 (m, 4H), 2.50 (m, 2H), 2.60 (m, 2H), 2.70 (m, 2H), 2.86 (m, 1H), 3.50 (m, 1H), 3.52-3.72 (m, 4H), 3.58 (s, 3H), 3.74-3.84 (m, 2H), 3.95 (m, 1H), 4.00-4.22 (m, 7H), 4.04 (m, 1H), 4.38 (m, 1H), 4.56 (bm, 1H), 4.57 (s, 1H), 4.74 (s, 1H), 4.98 (m, 2H).

Example 8 Preparation of a Compound of Formula (ID) through C.26-C.27 Macrocyclization

(R)-4-((2S,3aS,5R,7aS)-2-(3-hydroxypropyl)-3a-(iodomethyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yl trifluoromethanesulfonate

A solution of 3-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)propyl pivalate (6.80 g, 10.9 mmol) in CH₂Cl₂ (68.0 mL) was cooled to −78° C. and treated with 1 M DIBAL in toluene (23.88 mL, 23.88 mmol) over 20 min, while maintaining the internal temperature below −70° C. The reaction mixture was stirred at −78° C. for 30 min. The reaction was quenched with methanol (4.39 mL), while maintaining the internal temperature below −60° C. After removing the cold bath, the mixture was treated with 1 N HCl (109 mL) and MTBE (102 mL) and stirred at ambient temperature for 20 min. The organic layer was separated, and the aqueous layer was extracted with MTBE (102 mL). The organic layers were combined, dried over MgSO₄, and concentrated to give the title compound (8.8 g, contaminated with toluene). ¹H NMR (400 MHz, CDCl₃) δ 1.14 (d, 3H), 1.22 (m, 1H), 1.45-1.70 (m, 8H), 1.72-1.90 (m, 2H), 2.42 (m, 1H), 2.83 (m, 1H), 3.40 (d, 1H), 3.46 (d, 1H), 3.55 (m, 1H), 3.65 (m, 2H), 3.79 (m, 1H), 4.22 (m, 1H), 5.03 (d, 1H), 5.10 (d, 1H).

(R)-4-((2S,3aS,5R,7aS)-3a-(iodomethyl)-2-(3-oxopropyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yl trifluoromethanesulfonate

A solution of (R)-4-((2S,3aS,5R,7aS)-2-(3-hydroxypropyl)-3a-(iodomethyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yl trifluoromethanesulfonate (2.64 g, 4.87 mmol) in CH₂Cl₂ (26.4 mL) was treated with Dess-Martin periodinane (3.10 g, 7.30 mmol) and stirred at rt for 1 h. The reaction was quenched with saturated aqueous NaHCO₃ (20 mL) and 20% Na₂SO₃ (20 mL) and extracted three times with MTBE (20 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane1=710 to 1/3) to give the title compound (970 mg, 56% for 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 1.14 (d, 3H), 1.15-1.30 (m, 2H), 1.45-1.70 (m, 5H), 1.72-1.90 (m, 2H), 2.32 (dd, 1H), 2.52 (m, 2H), 2.83 (m, 1H), 3.37 (d, 1H), 3.43 (d, 1H), 3.52 (m, 1H), 3.72 (m, 1H), 4.19 (m, 1H), 5.01 (d, 1H), 5.09 (d, 1H), 9.76 (s, 1H).

(3R)-4-((2S,3aS,5R,7aS)-2-((6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-3-hydroxyhex-4-en-1-yl)-3a-(iodomethyl) hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yl trifluoromethanesulfonate

A solution of (((2S,3R,4S,4aS,6R,8aS)-2-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3,4-diyl)bis(oxy))bis(tert-butyldimethylsilane) (1.295 g, 1.51 mmol) in THF (10.20 mL) was cooled to −78° C. and treated with 1.6 M n-BuLi in hexane (0.944 mL, 1.51 mmol), while maintaining the internal temperature below −60° C. After stirring at −78° C. for 15 min, the mixture was treated with a solution of magnesium bromide diethyl etherate (0.390 g, 1.51 mmol) in a mixture of THF (6 mL) and toluene (1 mL), while maintaining the internal temperature below −60° C., and stirred at −78° C. for 30 min. A solution of (R)-4-((2S,3aS,5R,7aS)-3a-(iodomethyl)-2-(3-oxopropyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yl trifluoromethanesulfonate (0.68 g, 1.258 mmol) in THF (6.80 mL) was added, and the resulting mixture was stirred at −78° C. for 3 h and slowly warmed to rt over 14 h. The reaction was quenched with saturated aqueous NH₄Cl (6.80 mL) and extracted twice with MTBE (0.150 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/3) to give the title compound (455 mg, 28%).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate

A solution of (3R)-4-((2S,3aS,5R,7aS)-2-((6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl) octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-3-hydroxyhex-4-en-1-yl)-3a-(iodomethyl)hexahydro-2H-furo[3,2-b]pyran-5-yl)-3-methylbut-1-en-2-yl trifluoromethanesulfonate (0.455 g, 0.358 mmol) in CH₂Cl₂ (4.55 mL) was treated with benzoyl chloride (0.083 mL, 0.72 mmol), triethylamine (0.15 mL, 1.1 mmol) and DMAP (4.4 mg, 0.036 mmol). The mixture was stirred at ambient temperature for 40 h. The reaction was quenched with water (4.6 mL) and extracted twice with MTBE (9.1 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/5) to give the title compound (316 mg, 64%). ¹H NMR (400 MHz, CDCl₃) δ −0.08-0.12 (multiple s, 18H), 0.55 (m, 6H), 0.81 (2s, 9H), 0.85-1.00 (m, 27H), 1.05-1.30 (m, 2H), 1.12 (d, 3H), 1.40-1.90 (m, 16H), 2.29 (m, 1H), 2.80 (m, 2H), 3.30-3.45 (m, 3H), 3.53 (m, 2H), 3.65 (m, 1H), 3.72 (m, 1H), 3.83 (m, 2H), 4.08 (m, 1H), 4.19 (m, 1H), 4.98 (m, 1H), 5.02 (m, 1H), 5.07 (m, 1H), 5.60 (m, 1H), 5.77 (m, 1H), 6.05 (m, 1H), 7.40 (m, 2H), 7.52 (m, 1H), 8.02 (m, 2H).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-oxoethyl) octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate

A solution of oxalyl chloride (0.141 mL, 1.61 mmol) in CH₂Cl₂ (6.32 mL) was cooled to −78° C. and treated with DMSO (0.228 mL, 3.22 mmol). After stirring for 10 min at −78° C., the mixture was treated with a solution of (6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate (0.316 g, 0.230 mmol) in CH₂Cl₂ (3.8 mL). The mixture was stirred at −78° C. for 20 min and at −40° C. for 1 h. After cooling to −78° C., the mixture was treated with triethylamine (1.12 mL, 8.04 mmol) and stirred at −78° C. for 10 min and at 0° C. for 20 min. The reaction mixture was treated with water (6.3 mL) and diluted with MTBE (6.32 mL). The organic layer was separated and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give the title compound (284 mg).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl) tetrahydrofuran-3-yl)-2-hydroxy-3-(phenylsulfonyl)propyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate

A solution of (S)-5-(((2R,3R,4S,5S)-3-methoxy-4-((phenylsulfonyl)methyl)-5-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-2-yl)methyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (0.214 g, 0.298 mmol) in THF (3 mL) was cooled to −5° C. The mixture was treated with 1.6 M n-BuLi in hexane (0.186 mL, 0.298 mmol) and stirred at −5° C. for 20 min. After cooling to −78° C., the mixture was treated with a solution of (6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-3,4-bis((tert-butyldimethylsilyl)oxy)-6-(2-oxoethyl)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate (0.150 g, 0.119 mmol) in n-heptane (4.2 mL). The mixture was stirred at −78° C. for 4 h. The reaction was quenched with saturated aqueous NH₄Cl (7.5 mL) and extracted twice with MTBE (15 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/20 to 1/2) to give the title compound (177 mg, 75%).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl) tetrahydrofuran-3-yl)-2-oxo-3-(phenylsulfonyl)propyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate

A solution of (6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-3-yl)-2-hydroxy-3-(phenylsulfonyl)propyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate (0.177 g, 0.09 mmol) in CH₂Cl₂ (3.54 mL) was treated with sodium bicarbonate (0.011 g, 0.13 mmol) and Dess-Martin periodinane (0.057 g, 0.13 mmol) and stirred at rt for 1 h. Additional Dess-Martin periodinane (0.019 g, 0.045 mmol) was added, and stirring was continued at rt for another 1 h. The reaction was quenched with saturated aqueous NaHCO₃ (3.5 mL) and 20% Na₂SO₃ (3.5 mL) and extracted twice with MTBE (3.5 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/3) to give the title compound (170 mg, 96%).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-3-yl)-2-oxopropyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate

A solution of (6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl) oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-3-yl)-2-oxo-3-(phenylsulfonyl)propyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate (0.17 g, 0.086 mmol) in a mixture of THF (1.4 mL) and methanol (0.85 mL) was cooled to −78° C. and treated with 0.1 M SmI₂ in THF (1.29 mL, 0.129 mmol). After stirring at −78° C. for 1 h, additional 0.1 M SmI₂ in THF (0.86 mL, 0.086 mmol) was added, and stirring was continued at −78° C. for another 2 h. The reaction was quenched with a mixture of Rochelle's Salt (510 mg, 1.807 mmol), potassium carbonate (509 mg, 3.69 mmol), and water (5.1 mL) and extracted twice with MTBE (8.5 mL). The organic layers were combined and dried over MgSO₄ to give the title compound (127 mg, 80%).

(6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-oxoethyl)tetrahydrofuran-3-yl)-2-oxopropyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate

A solution of oxalyl chloride (0.061 mL, 0.69 mmol) in CH₂Cl₂ (2.54 mL) was cooled to −78° C. and treated with DMSO (0.098 mL, 1.4 mmol). After stirring at −78° C. for 10 min, a solution of (6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-2-(2-((triethylsilyl)oxy)ethyl)tetrahydrofuran-3-yl)-2-oxopropyl)-3,4-bis((tert-butyldimethylsilyl) oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy)but-3-en-1-yl) hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate (0.127 g, 0.069 mmol) in CH₂Cl₂ (2.5 mL) was added. The resulting solution was stirred at −78° C. for 10 min and at −40° C. for 1 h. After cooling to −78° C., the mixture was treated with triethylamine (0.5 mL, 3.6 mmol) and stirred at −78° C. for 10 min and at 0° C. for 20 min. The mixture was treated with water (5 mL) and extracted twice with MTBE (10 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/5) to give the title compound (86 mg, 72%).

NHK Macrocyclization

(S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl) methanesulfonamide (0.829 g, 2.797 mmol) was dissolved in a degassed acetonitrile (7.12 mL) and treated with chromous chloride (0.346 g, 2.82 mmol). After purging with nitrogen gas for 5 min, the mixture was heated to 30° C. and treated with Et₃N (0.39 mL, 2.8 mmol). The mixture was stirred at 34° C. for 1 h. After cooling to 0° C., the mixture was treated with nickel chloride (6.7 mg, 0.052 mmol) and purged with nitrogen gas for 5 min. After removing the ice-bath, the mixture was treated with a solution of (6S,E)-6-((2S,3R,4S,4aS,6R,8aS)-6-(3-((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy) propyl)-4-methoxy-2-(2-oxoethyl)tetrahydrofuran-3-yl)-2-oxopropyl)-3,4-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)-6-((tert-butyldimethylsilyl)oxy)-1-((2S,3aS,5R,7aS)-3a-(iodomethyl)-5-((R)-2-methyl-3-(((trifluoromethyl)sulfonyl)oxy) but-3-en-1-yl)hexahydro-2H-furo[3,2-b]pyran-2-yl)hex-4-en-3-yl benzoate (0.089 g, 0.052 mmol) in a mixture of THF (3.1 mL) and acetonitrile (1.4 mL) over 40 min via syringe pump. The mixture was stirred at 20° C. for another 2 h. The mixture was diluted with n-heptane (8.90 mL), filtered to remove insoluble residue, and washed with n-heptane (8.90 mL). The heptane layer was separated, and the acetonitrile layer was extracted with n-heptane (8.9 mL). The heptane layers were combined and washed twice with acetonitrile (8.90 mL). After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give the compound 19 (18 mg and 11 mg of two products epimeric at C.14, total 36%). Mass [M+NH₄]=1587.0 and 1586.9, respectively for two products (calc. 1586.8).

Acetylation

A solution of compound 19 (0.029 g, 0.018 mmol) in CH₂Cl₂ (3 mL) was treated with acetic anhydride (0.012 mL, 0.13 mmol), triethylamine (0.026 mL, 0.19 mmol) and DMAP (0.226 mg, 1.85 μmol). After stirring for 1 h at rt, additional triethylamine (0.026 mL, 0.19 mmol), acetic anhydride (0.012 mL, 0.13 mmol), and DMAP (0.226 mg, 1.85 μmol) were added, and stirring was continued at rt for another 3 h. The reaction was quenched with water and extracted twice with MTBE. The organic layers were combined and dried over MgSO₄. After concentration, the residue was filtered through silica gel pad, and the filtrate was concentrated in vacuo to give compound 20 (30 mg).

Vasella Fragmentation

A solution of compound 20 (0.030 g, 0.019 mmol) in THF (1.2 mL) was treated with water (0.3 mL), zinc dust (0.036 g, 0.56 mmol), and acetic acid (0.021 mL, 0.37 mmol). The mixture was stirred at rt for 2 h. Additional zinc dust (0.036 g, 0.56 mmol) and acetic acid (0.021 mL, 0.37 mmol) were added, and stirring was continued at rt for 15 h. The mixture was diluted with MTBE (30 mL) and filtered through a Celite® pad to remove insoluble solid. The filtrate was washed twice with saturated aqueous NaHCO₃ (5 mL), dried over MgSO₄, and concentrated in vacuo to give compound 21 (27 mg).

Mesylation

A solution of compound 21 (0.027 g, 0.018 mmol) in THF (2 mL) was cooled to 0° C. and treated with MsCl (5.7 μL, 0.073 mmol) and triethylamine (0.020 mL, 0.15 mmol). The mixture was stirred at 0° C. for 1 h. The reaction was quenched with water (4 mL) and extracted twice with MTBE (8 mL). The organic layers were combined, dried over MgSO₄, and concentrated in vacuo to give compound 22 (27 mg).

Cyclization with KOMe

A solution of compound 23 (0.027 g, 0.017 mmol) in THF (3 mL) was cooled to 0° C. and treated with 25% potassium methoxide in methanol (0.025 mL, 0.086 mmol). The mixture was stirred at 0° C. for 3 h and slowly warmed to 15° C. over 14 h. The reaction was quenched with saturated aqueous NH₄Cl (2.70 mL) and extracted with MTBE (8.10 mL). The organic layer was separated, dried over MgSO₄, and concentrated in vacuo to give compound 24 (23 mg).

Oxidation to a Conjugate Ketone

A solution of compound 24 (0.023 g, 0.017 mmol) in CH₂Cl₂ (2 mL) was treated with Dess-Martin periodinane (0.015 g, 0.035 mmol) and stirred at rt for 30 min. The reaction was quenched with saturated aqueous NaHCO₃ (2 mL) and 20% Na₂SO₃ (2 mL) and extracted with MTBE (2 mL). The organic layer was dried over MgSO₄. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/5) to give compound 25 (1 mg). The structure was confirmed by comparison of the ¹H NMR spectrum with that of an authentic sample. ¹H NMR (400 MHz, C₆D₆) δ −0.08 (s, 3H), 0.02 (s, 12H), 0.03 (s, 3H), 0.04 (s, 3H), 0.11 (s, 3H), 0.13 (s, 3H), 0.18 (s, 3H), 0.85 (s, 27H), 0.92 (s, 9H), 0.95 (s, 9H), 1.01 (m, 1H), 1.05 (d, 3H), 1.20-1.45 (m, 4H), 1.53 (m, 3H), 1.60-1.85 (m, 7H), 1.92 (m, 2H), 2.03 (m, 1H), 2.25 (m, 2H), 2.48 (m, 2H), 2.60-2.78 (m, 4H), 2.84 (dd, 1H), 2.93 (dd, 1H), 3.29 (s, 3H), 3.39 (m, 2H), 3.48 (m, 1H), 3.53 (m, 2H), 3.66 (m, 1H), 3.77 (m, 1H), 3.70-3.80 (m, 4H), 4.01 (d, 1H), 4.05 (s, 2H), 4.22 (m, 1H), 4.75 (s, 1H), 4.82 (s, 1H), 4.88 (s, 1H), 4.98 (s, 1H), 4.99 (m, 1H), 6.33 (d, 1H), 7.25 (dd, 1H).

Example 9 Preparation of a Compound of Formula (ID) Through a C.0-C.1 Macrocyclization

(S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)propane-1,2-diyl bis(4-nitrobenzoate)

A solution of (S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)propane-1,2-diol (1.90 g, 4.54 mmol) was dissolved in CH₂Cl₂ (19 mL) and treated with pyridine (2.203 mL, 27.24 mmol) and 4-nitrobenzoyl chloride (2.53 g, 13.6 mmol). The mixture was stirred at rt for 20 h and at 40° C. for 20 h. Additional 4-nitrobenzoyl chloride (0.842 g, 4.54 mmol) and pyridine (0.734 mL, 9.08 mmol) were added, and stirring was continued at 40° C. for another 1 d. The reaction was quenched with water (25 mL), filtered to remove insoluble solid, and extracted twice with MTBE (25 mL). The organic layers were combined, washed with 1 N HCl (20 mL) and with saturated aqueous NaHCO₃ (15 mL), and dried over MgSO₄. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/1) to give the title compound (2.05 g, 77% for 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 1.85 (t, 2H), 2.19 (m, 1H), 2.30 (m, 1H), 2.55 (m, 1H), 3.02 (dd, 1H), 3.09 (dd, 1H), 3.19 (s, 3H), 3.21 (s, 3H), 3.41 (s, 3H), 3.58 (q, 1H), 3.88 (m, 1H), 3.96 (m, 1H), 4.32 (m, 1H), 4.62 (m, 2H), 5.69 (m, 1H), 7.57 (m, 2H), 7.66 (m, 1H), 7.89 (m, 2H), 8.13 (d, 2H), 8.18 (d, 2H), 8.25 (m, 4H).

Triethyl(((S)-5-methyl-1-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl) tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl)oxy)silane

A mixture of Pd₂(dba)₃ (5.7 mg, 6.2 μmol) and (S)-(−)-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl (0.012 g, 0.025 mmol) was purged with nitrogen for 5 min, treated with n-heptane (1 mL), and stirred at rt for 10 min. After addition of Hünig's base (0.11 mL, 0.62 mmol) and a solution of (3R,5R)-3-methyl-7-((2S,5S)-3-methylene-5-(3-((triethylsilyl)oxy)propyl)tetrahydrofuran-2-yl)-5-((triethylsilyl)oxy)hept-1-en-2-yl trifluoromethanesulfonate (0.20 g, 0.31 mmol) in n-heptane (2 mL), the mixture was stirred at rt for 20 h, at 35° C. for 2 d, and at 50° C. for 1 d. The mixture was cooled to rt, filtered through a Celite® pad to remove the catalyst, and the pad was rinsed with n-heptane. The colorless filtrate was concentrated in vacuo to give the title compound (a 1:1 mixture of SM and the allene).

3-((2S,5S)-5-((R)-3-hydroxy-5-methylhepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate

3-((2S,5S)-5-((3R,5R)-3-hydroxy-5-methyl-6-(((trifluoromethyl)sulfonyl)oxy)hept-6-en-1-yl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate (90.0 g, 180 mmol) was dissolved in 1,2-dichloroethane (900 mL) and treated with 1-methylimidazole (25.8 mL, 323.632 mmol). The mixture was stirred at 85° C. for 5 h. After cooling to rt, the mixture was diluted with MTBE (1.8 L), sequentially washed with 1.0 M HCl in water (500 mL), water (200 mL), saturated aqueous sodium bicarbonate (150 mL), and brine (150 mL), and dried over Na₂SO₄. After concentration, the residue was purified by column chromatography (ethyl acetate/n-heptane=3/7) to give a mixture of the allene and acetylene. The mixture was further purified by prep. HPLC to give the title compound (20 g, 31%). ¹H NMR (400 MHz, CDCl₃) δ 1.10 (s, 9H), 1.40-1.80 (m, 8H), 1.72 (s, 3H), 2.10 (m, 2H), 2.27 (dd, 1H), 2.46 (bs, 1H), 2.70 (dd, 1H), 3.80 (m, 1H), 4.08 (m, 3H), 4.39 (bm, 1H), 4.66 (m, 2H), 4.87 (s, 1H), 5.00 (s, 1H).

(S)-5-methyl-1-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl 4-nitrobenzoate

3-((2S,5S)-5-((R)-3-hydroxy-5-methylhepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate (6.94 g, 19.8 mmol) was dissolved in toluene (35.4 mL) and treated with 4-nitrobenzoic acid (4.30 g, 25.7 mmol) and triphenylphosphine (6.75 g, 25.7 mmol). After cooling to 0° C., the mixture was charged with DIAD (4.62 mL, 23.7 mmol) and stirred at 0° C. for 2.5 h. The mixture was diluted with MTBE (156 mL) and washed with saturated aqueous NaHCO₃ (39.0 mL). After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/9) to give the title compound (9.9 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ 1.19 (s, 9H), 1.49 (m, 1H), 1.53-1.80 (m, 5H), 1.73 (s, 3H), 1.88 (m, 2H), 2.28 (m, 2H), 2.41 (m, 1H), 2.68 (m, 1H), 4.02 (m, 1H), 4.08 (m, 2H), 4.40 (m, 1H), 4.45 (m, 1H), 4.52 (m, 1H), 4.81 (s, 1H), 4.99 (s, 1H), 5.34 (m, 1H), 8.20 (m, 2H), 8.30 (m, 2H).

3-((2S,5S)-5-((S)-3-hydroxy-5-methylhepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate

(S)-5-methyl-1-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl 4-nitrobenzoate (9.90 g, 19.8 mmol) was dissolved in a mixture of THF (100 mL) and water (50 mL) and treated with lithium hydroxide monohydrate (2.50 g, 59.4 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was diluted with brine (118 mL) and extracted with MTBE (470 mL). The organic layer was concentrated and purified by silica gel column chromatography (ethyl acetate/n-heptane=15/85) to give the title compound (5.55 g, 80%). ¹H NMR (400 MHz, CDCl₃) δ 1.20 (s, 9H), 1.40-1.80 (m, 9H), 1.65 (s, 3H), 2.10 (m, 2H), 2.25 (dd, 1H), 2.68 (dd, 1H), 3.79 (m, 1H), 4.05 (m, 2H), 4.40 (m, 1H), 4.62 (m, 2H), 4.85 (s, 1H), 5.00 (s, 1H).

(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-(2-methoxyacetoxy)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)propane-1,2-diyl bis(4-nitrobenzoate)

A mixture of 3-((2S,5S)-5-((S)-3-hydroxy-5-methylhepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate (0.200 g, 0.571 mmol) and (S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diylbis(4-nitrobenzoate) (0.573 g, 0.799 mmol) was dissolved in CH₂Cl₂ (8.0 mL) and cooled to −30° C. The mixture was sequentially treated with methoxyacetic acid (0.657 mL, 8.56 mmol) and then BF₃—OEt₂ (0.217 mL, 1.71 mmol) and stirred between −30° C. and −20° C. for 7 h. The reaction was quenched with saturated aqueous NaHCO₃ (14.4 mL) and extracted twice with MTBE (10 mL). The organic layers were combined and washed with brine. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 2/3) to give the title compound (518 mg, 83%). ¹H NMR (400 MHz, CDCl₃) δ 1.18 (s, 9H), 1.40-1.74 (m, 8H), 1.70 (s, 3H), 1.76-1.96 (m, 4H), 2.16-2.34 (m, 3H), 2.60-2.70 (m, 2H), 3.00 (dd, 1H), 3.16 (dd, 1H), 3.34 (m, 1H), 3.42 (s, 3H), 3.45 (s, 3H), 3.61 (m, 1H), 3.82 (m, 1H), 3.94-3.46 (m, 7H), 4.26 (m, 1H), 4.52 (d, 1H), 4.58-4.69 (m, 3H), 4.73 (s, 1H), 4.92 (s, 1H), 5.66 (m, 1H), 7.58 (m, 2H), 7.62 (m, 1H), 7.90 (m, 2H), 8.1-8.3 (m, 8H).

(S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl bis(4-nitrobenzoate)

A mixture of Pd(Ph₃P)₄ (0.024 g, 0.021 mmol) and triphenylphosphine (0.022 g, 0.084 mmol) in THF (2.3 mL) (in a vial with a cap) was heated to 60° C. and stirred for 5 min. The mixture was treated with a mixture of (S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-(2-methoxyacetoxy)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diylbis(4-nitrobenzoate) (0.230 g, 0.21 mmol), formic acid (0.040 mL, 1.1 mmol) and triethylamine (0.147 mL, 1.05 mmol) in THF (3.4 mL). The mixture was stirred at 60° C. (bath) for 46 h. After cooling to rt, the mixture was treated with water (10.5 mL) and extracted twice with MTBE (10.5 mL). The organic layers were combined and washed with brine (10 mL). After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give the title compound (148 mg, 70%). ¹H NMR (400 MHz, CDCl₃) δ 1.06 (d, 3H), 1.18 (s, 9H), 1.24-1.68 (m, 8H), 1.68-1.80 (m, 2H), 1.86 (m, 1H), 2.04-2.28 (m, 4H), 2.56 (m, 1H), 2.58-2.68 (m, 2H), 3.05 (m, 2H), 3.36 (m, 1H), 3.46 (s, 3H), 3.58 (dd, 1H), 3.73 (m, 1H), 3.85 (m, 1H), 3.95 (m, 1H), 4.01 (m, 1H), 4.06 (m, 2H), 4.23 (m, 1H), 4.60-4.72 (m, 3H), 4.78 (s, 2H), 4.92 (s, 1H), 5.72 (m, 1H), 7.62 (m, 2H), 7.70 (m, 1H), 7.97 (m, 2H), 8.1-8.3 (m, 8H).

3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate

A solution of (S)-3-((2R,3R,4S,5S)-3-methoxy-5-(((2R,4R,6S)-4-methyl-3-methylene-6-(2-((2S,5S)-3-methylene-5-(3-(pivaloyloxy)propyl)tetrahydrofuran-2-yl)ethyl)tetrahydro-2H-pyran-2-yl)methyl)-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl bis(4-nitrobenzoate) (1.90 g, 1.89 mmol) in a mixture of THF (1.9 mL) and methanol (38 mL) was treated with 6-10% Mg(OMe)₂ in methanol (2.07 mL, 1.13 mmol). The mixture was stirred at rt for 2 h. The reaction was quenched with saturated aqueous NH₄Cl (19 mL), concentrated to remove methanol, and extracted three times with ethyl acetate (19 mL). The organic layers were combined and dried over MgSO₄. After concentration, the residue was purified by column chromatography (ethyl acetate/n-heptane=1/10 to 2/1) to give the title compound (934 mg, 70%). ¹H NMR (400 MHz, CDCl₃) δ 1.08 (d, 3H), 1.20 (s, 9H), 1.34-1.84 (m, 11H), 1.90-2.06 (m, 2H), 2.14-2.26 (m, 3H), 2.58-2.68 (m, 2H), 3.04-3.16 (m, 2H), 3.41 (m, 1H), 3.46 (s, 3H), 3.56 (dd, 1H), 3.60 (m, 1H), 3.66 (dd, 1H), 3.83 (m, 1H), 3.92 (s, 2H), 3.92-4.00 (m, 2H), 4.07 (m, 2H), 4.26 (bm, 1H), 4.68 (d, 1H), 4.80 (d, 1H), 4.85 (s, 1H), 4.92 (s, 1H), 7.62 (m, 2H), 7.70 (m, 1H), 7.99 (m, 2H).

3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl) ethyl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate

A solution of 3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate (0.040 g, 0.057 mmol) in DMF (1 mL) was treated with imidazole (0.019 g, 0.28 mmol) and TBSCl (0.026 g, 0.17 mmol), and stirred at rt for 3 h. Additional TBSCl (0.026 g, 0.17 mmol) and imidazole (0.019 g, 0.28 mmol) were added, and stirring was continued at rt for 3 d. The reaction was quenched with water (4 mL) and diluted with MTBE (5 mL). The organic layer was separated, washed twice with water (4 mL), and dried over MgSO₄ to give the title compound (40 mg).

3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl) oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propan-1-ol

A solution of 3-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl) tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propyl pivalate (0.040 g, 0.043 mmol) in toluene (1.5 mL) was cooled to −78° C. and treated with 1.5 M DIBAL in toluene (0.114 mL, 0.171 mmol). The mixture was stirred at −78° C. for 30 min. Additional 1.5 M DIBAL in toluene (0.057 mL, 0.086 mmol) was added and stirring was continued at −78° C. for another 1 h. The reaction was quenched with 1 N HCl (1 mL) and MTBE (10 mL) and stirred at rt for 1 h. The organic layer was separated and sequentially washed with water (5 mL), saturated aqueous NaHCO₃ (5 mL), and brine (3 mL). After concentration, the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane=1/10 to 2/3) to give the title compound (13 mg, 60% for 3 steps). ¹H NMR (400 MHz, CDCl₃) 0.02 (s, 6H), 0.04 (s, 6H), 0.88 (s, 18H), 1.02 (d, 3H), 1.34-1.48 (m, 2H), 1.48-1.70 (m, 6H), 1.76 (m, 1H), 1.80-1.94 (m, 3H), 2.02 (m, 1H), 2.14-2.28 (m, 3H), 2.56 (m, 1H), 2.64 (m, 1H), 3.20 (m, 2H), 3.40 (m, 1H), 3.43 (s, 3H), 3.48 (dd, 1H), 3.65-3.72 (m, 5H), 3.76-3.86 (m, 3H), 3.98 (m, 1H), 4.30 (m, 1H), 4.68 (s, 1H), 4.78 (s, 1H), 4.86 (s, 1H), 4.92 (s, 1H), 7.60 (m, 2H), 7.70 (m, 1H), 8.21 (m, 2H).

3-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propan-1-al

3-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propan-1-ol 26 (5.72 g, 6.721 mmol) was dissolved in DCM (43.3 mL, 673.711 mmol) and water (0.036 mL, 2.016 mmol) was added. Dess-Martin Periodinane (DMP) (3.60 g, 8.488 mmol) was added in portions over 4 minutes, while maintaining the temperature below 25° C., and the reaction was monitored by TLC (MTBE and silica gel). Additional DMP (2.550 g, 5.012 mmol) was added, and the reaction was stirred until compound 26 was consumed. Saturated aqueous sodium bicarbonate (50 mL) was added followed by 10% aqueous sodium thiosulfate (50 mL). The mixture was partitioned and the aqueous layer extracted twice with dichloromethane (DCM). The combined DCM extracts were washed with water, and the solution was dried over sodium sulfate and concentrated to provide 27 (5.63 g, 99% yield) as an orange oil that was used as is in the next step.

Methyl 2-((2R,4aS,6S,7R,8S,8aS)-6-((1 S,E)-6-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxyhex-2-en-1-yl)-7,8-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)acetate

(S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide (3.84 g, 12.94 mmol) was added to a three-neck flask fitted with 3-way stopcock, septum, and solid addition pistol. Chromium(II) chloride (1.59 g, 12.94 mmol) was added to the solid addition pistol, and the apparatus was purged with nitrogen (3× vacuum/N₂-back-flush through the 3-way stopcock). Tetrahydrofuran (17.58 mL) was added. CrCl₂ was added in portions to the vigorously stirred solution. The resulting suspension was warmed to 30° C., and TEA (1.85 mL, 12.94 mmol) was added. The solution was stirred for 60 minutes before cooling to 0° C. [(2,9-dimethyl-1,10-phenanthroline)dichloronickel(II)] complex (0.224 g, 0.663 mmol) in tetrahydrofuran (2.5 mL) was added followed by a mixture of 3-((25)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)propanal 27 (2.198 g, 2.588 mmol) and methyl 2-((2R,4aS,6S,7R,8S,8aS)-7,8-bis((tert-butyldimethylsilyl)oxy)-6-((S,E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)acetate (2.394 g, 3.106 mmol) in THF (4.4 mL) was added. The reaction was warmed to RT and monitored by TLC and HPLC. Upon completion, the reaction was cooled to 5-10° C. and ethylenediamine (2.184 mL, 25.88 mmol) was added. The mixture was stirred for 1 hour, and then n-heptane (25 mL) and water (25 mL) were added. The layers were separated and the aqueous layer was extracted twice with n-heptane (25 mL). The combined organic layers were combined and washed with aqueous hydrogen chloride (1.0N, 25 mL), water (25 mL), saturated aqueous sodium bicarbonate (25 mL), and saturated aqueous sodium chloride (25 mL). The solution was dried with sodium sulfate, filtered, and partially concentrated in vacuo. The precipitate of (S)-N-(2-(4-isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide was filtered, and the cake was washed with heptane (20 mL). The filtrate and wash were concentrated to dryness, and the crude product was purified on Biotage® Snap KP-Sil 100 g cartridge conditioned with heptane (4 CV). The crude product was loaded with heptane and eluted with heptane/ethyl acetate (9:1, 4:1, 7:3, and 1:1 heptane/ethyl acetate, 5 CV each). The fractions containing product were pooled to provide 28 (2.773 g, 72%) as a pale yellow oil upon removal of volatiles in vacuo.

Methyl 2-((2R,4aS,6S,7R,8S,8aS)-6-((1S,E)-6-((2S)-5-(2-((2S,4R,6R)-6-M2S,3S,4R,5R)-5- ((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-oxohex-2-en-1-yl)-7,8-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)acetate

Methyl 2-((2R,4aS,6S,7R,8S,8aS)-6-((1 S,E)-6-((25)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxyhex-2-en-1-yl)-7,8-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)acetate 28 (2.773 g, 0.1.856 mmol) was dissolved in DCM (13.4 mL), and water (1.67 μL, 0.093 mmol) was added. Dess-Martin periodinane (0.944 g, 2.227 mmol) was added in portions, while maintaining the temperature below 22° C. When the reaction was deemed complete, 25 mL saturated aqueous sodium bicarbonate was added followed by 10% aqueous sodium thiosulfate (25 mL). The mixture was stirred for 20 minutes, and the layers partitioned. The aqueous layer was extracted with dichloromethane (DCM) (2×40 mL). The combined organic layers were concentrated in vacuo to provide 29 (2.688 g, 1.8 mmol, 97% yield). ¹H NMR (400 MHz, CDCl₃) δ: 7.92 (dd, 2H), 7.68 (t, 1H), 7.60 (t, 2H), 7.55-7.63 (m, 2H), 7.08 (dd, 1H), 6.29 (d, 1H), 5.08-5.14 (m, 1H), 4.85-4.89 (m, 1H), 4.83 (s, 1H), 4.76 (s, 1H), 4.62 (d, 1H), 4.17-4.24 (m, 1H), 4.07 (s, 1H), 3.87-4.02 (m, 1H), 3.83 (s, 4H), 3.65-3.66 (m, 3H), 3.65 (s, 3H), 3.62-3.69 (m, 2H), 3.52-3.61 (m, 2H), 3.47 (dd, 1H), 3.41-3.42 (m, 3H), 3.41 (s, 3H), 3.25-3.43 (m, 6H), 2.95-3.06 (m, 1H), 2.90 (dd, 1H), 2.44-2.73 (m, 4H), 2.30-2.37 (m, 1H), 2.12-2.24 (m, 2H), 1.95-2.02 (m, 1H), 1.63-1.92 (m, 6H), 1.13-1.58 (m, 5H), 1.02-1.08 (m, 3H), 1.05 (d, 3H), 0.98-1.10 (m, 3H), 0.93-0.95 (m, 2H), 0.94 (s, 9H), 0.92 (s, 9H), 0.87 (s, 18H), 0.89-0.85 (m, 2H), 0.85 (s, 9H), 0.12 (s, 3H), 0.11 (s, 3H), 0.08 (s, 3H), 0.08 (s, 3H), 0.03 (s, 3H).

Methyl 2-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

Methyl 2-((2R,4aS,6S,7R,8S,8aS)-6-((1 S,E)-6-((2S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)-1-((tert-butyldimethylsilyl)oxy)-4-oxohex-2-en-1-yl)-7,8-bis((tert-butyldimethylsilyl)oxy)octahydropyrano[3,2-b]pyran-2-yl)acetate 29 (4.26 g, 2.854 mmol) was dissolved in THF (63.9 mL, 779.855 mmol) and N,N-dimethylacetamide (21.30 mL, 227.375 mmol). Imidazole hydrochloride (0.880 g, 8.421 mmol) was added followed by TBAF in THF (18.55 mL, 18.554 mmol). The reaction was monitored by TLC (silica gel; 1:1 MTBE/heptane and 9:1 EtOAc/MeOH) and stirred for 10 d. When the reaction was deemed complete, the reaction mixture was concentrated in vacuo at RT, and the residue was dissolved in ethanol (90 mL). 1H-imidazole hydrochloride (2.510 g, 24.007 mmol) and water (42.6 mL, 2364.659 mmol) were added, and the reaction was monitored by TLC for the formation of compound 30. After 24 h, an additional portion of imidazole hydrochloride (2.5 g) was added, and the solution was stirred for 72 h. Aqueous saturated sodium bicarbonate was added followed by toluene, and the mixture was concentrated in vacuo to remove EtOH. The residue was diluted with 30 volumes of 2:1 (v/v) THF/toluene, and the phases separated. The aqueous layer was extracted with 10 volumes of 1:1 (v/v) THF/toluene. The combined organic layers were washed with water (2×10 volumes), dried with sodium sulfate, and concentrated in vacuo. The residue was purified on Biotage® with 300 g HP-Sil cartridge using 2:1 toluene/acetonitrile (1 L), 1:1 toluene/acetonitrile (2 L), and 9:1 acetonitrle/MeOH. Fractions containing compound 30 were pooled and concentrated in vacuo to provide 1.8 g product. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, 2H), 7.68 (t, 1H), 7.60 (t, 2H), 4.89 (d, 1H), 4.82 (s, 1H), 4.77 (s, 1H), 4.68-4.65 (m, 2H), 4.60-4.57 (m, 1H), 4.42-4.40 (m, 1H), 4.29-4.22 (m, 2H), 4.18 (dd, 1H), 4.05 (dd, 1H), 3.98-3.88 (m, 4H), 3.80 (td, 2H), 3.64 (s, 3H), 3.70-3.49 (m, 1H), 3.42 (s, 3H), 3.38-3.28 (m, 2H), 3.15-3.00 (m, 2H), 2.91 (dd, 1H), 2.65-2.54 (m, 3H), 2.38 (d, 1H), 2.34 (d, 1H), 2.24-2.12 (m, 6H), 2.11-1.84 (m, 5H), 1.84-1.57 (m, 6H), 1.56-1.45 (m, 2H), 1.44-1.26 (m, 4H), 1.09-0.97 (m, 4H).

Methyl 2-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

Methyl 2-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-dihydroxypropyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate 30 (0.734 g, 0.813 mmol) was dissolved in dichloromethane (DCM) (7.34 mL, 114.076 mmol). 2,6-Lutidine (0.568 mL, 4.877 mmol) was added the solution, which was then cooled to 0° C. tert-Butyldimethylsilyl trifluoromethanesulfonate (0.467 mL, 2.032 mmol) was added, and the reaction was stirred and monitored for completion by TLC. Upon completion of the reaction, aqueous saturated sodium bicarbonate was added, and the mixture was stirred for 15 minutes. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed sequentially with water, 0.1 N HCl, water, and aqueous saturated sodium bicarbonate. The combined organic layers were concentrated in vacuo to provide a yellow oil. The product was purified by suction silica gel column chromatography (14 g SiO₂, 230-400 m). The crude reaction mixture was loaded with DCM/heptane, and the column was eluted with heptane/MTBE (1:1 (v/v), 150 mL) followed by MTBE (2×150 mL). The fractions containing the product were pooled and concentrated in vacuo to provide 31 (848 mg) of white foam. ¹H NMR (400 MHz, C₆D₆) δ=7.96-7.90 (m, 2H), 7.08-7.02 (m, 3H), 4.88-4.84 (m, 1H), 4.82-4.78 (m, 1H), 4.76-4.71 (m, 1H), 4.66-4.62 (m, 1H), 4.52-4.42 (m, 1H), 4.39-4.29 (m, 2H), 4.15-4.04 (m, 4H), 4.03-3.84 (m, 5H), 3.81-3.60 (m, 6H), 3.45 (s, 3H), 3.27 (s, 3H), 3.16-3.08 (m, 1H), 2.94 (s, 2H), 2.58-2.48 (m, 3H), 2.48-2.34 (m, 2H), 2.30-1.87 (m, 12H), 1.00 (s, 9H), 0.94 (s, 9H), 0.96-0.90 (m, 2H), 0.93 (d, J=2.0 Hz, 1H), 0.93 (d, J=1.6 Hz, 1H), 0.89-0.81 (m, 8H), 0.19 (s, 2H), 0.17 (s, 3H), 0.06 (s, 3H), 0.06 (s, 3H)

Bis-TBS Ether Phenylsulfone 32

Treat methyl 2-((2S,3aR,4aR,5S,5aS,7R,9aS,10aR,10bS)-2-(2-((2S,5S)-5-(2-((2S,4R,6R)-6-(((2S,3S,4R,5R)-5-((S)-2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-4-methoxy-3-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)methyl)-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl)-4-methylenetetrahydrofuran-2-yl)ethyl)dodecahydro-2,5-epoxyfuro[2′,3′:4,5]furo[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate 31 in a solvent (e.g., THF, 2-methyltetrahydrofuran, MTBE, DME, toluene, chlorobenzene, tert-butanol, isopropanol, or another solvent) (30-100 volumes) with a base (e.g., potassium t-butoxide, KHMSA, potassium pentoxide, or a similar base) (1-5 equiv.). The resulting mixture is stirred at a temperature between −20° C. and reflux and is monitored for consumption of starting material. The reaction can be quenched by addition of 0.1 N HCl (10 volumes). The mixture can be extracted with MTBE or other suitable organic solvent. The organic layers can be combined and washed sequentially with water, saturated aqueous sodium bicarbonate, and water. The resulting organic solution can be dried over Na₂SO₄, filtered, and concentrated in vacuo to provide 32. The product can be purified by chromatography if necessary.

Bis TBS-Ether 18

Compound 32 was dissolved in THF (0.35 mL) and MeOH (0.25 mL), and the solution was cooled to −78° C. Samarium (II) iodide (1.0 M in THF, 0.12 mL, 2.5 eq) was added, and the reaction was monitored by TLC. The reaction progressed to approximately 50% completion. Additional samarium (II) iodide was added (1.0M in THF, 0.6 mL, 12.5 eq) in portions over 1 h. The reaction conversion remained at 50%. The reaction mixture was worked up by the addition of Rochelle salt/potassium carbonate/water (1:1:10 ratio; 20 mL) and extracted with EtOAc (3×20 mL). The combined extracts were sequentially washed with saturated sodium bicarbonate, water, and brine before drying with sodium sulfate. After filtering, the filtrate is concentrated in vacuo to provide a residue of 18 and 32. ¹H NMR analysis against an authentic sample of 18 confirmed the structural assignment.

Other Embodiments

Various modifications and variations of the described device and methods of use of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.

Other embodiments are in the claims. 

1. A method of preparing an intermediate in the synthesis of eribulin, said method comprising performing a macrocyclization reaction on a non-macrocyclic intermediate, said macrocyclization reaction producing said intermediate in the synthesis of eribulin by forming C.15-C.16, C.2-C.3, C.3-C.4, C.19-C.20, C.0-C.1, or C.26-C.27 bond in the structure of eribulin.
 2. The method of claim 1, wherein said performing said macrocyclization reaction comprises contacting said non-macrocyclic intermediate with an olefin metathesis catalyst.
 3. The method of claim 2, wherein said non-macrocyclic intermediate is a compound of formula (IA) or a salt thereof:

wherein R₁ is H or —CH₂X₁CH₂CH═CH₂, wherein X₁ is O, —C(R₉)₂—, or NP₅, and wherein each R₉ is independently H or —COOR₁₀, P₅ is an N-protecting group, and R₁₀ is C₁₋₆ alkyl; (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl ether, and R₄ is H; (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄ combine to form a double bond; or (a3) R₂ and R₃ combine to form a bond, and R₄ is H; (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇ combine to form a double bond; or (b2) R₅ and R₆ combine to form a bond, and R₇ is H; (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group; or (c2) R₈ and P₄ combine to form a double bond; each P₃ is independently H or a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; and wherein said intermediate in the synthesis of eribulin is a compound of formula (IB) or a salt thereof:


4. The method of claim 3, wherein each P₃ and P₄ is independently a hydroxyl protecting group.
 5. The method of claim 3 or 4, wherein at least one of P₁ and P₂ is a hydroxyl protecting group.
 6. The method of any one of claims 3 to 5, wherein R₂ and R₃ combine to form a bond, and R₄ is H.
 7. The method of any one of claims 3 to 6, wherein R₅ and R₆ combine to form a bond, and R₇ is H.
 8. The method of claim 1, wherein said performing said macrocyclization reaction comprises contacting said non-macrocyclic intermediate with an organic base and a Lewis acid.
 9. The method of claim 8, wherein said non-macrocyclic intermediate is a compound of formula (IIA) or a salt thereof:

wherein each R is independently optionally substituted alkyl or optionally substituted aryl; (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃ combine to form a double bond; or (ii) R₁ and R₂ combine to form a bond, and R₃ is H; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; P₄ is H or a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; and wherein said intermediate in the synthesis of eribulin is a compound of formula (IIB) or a salt thereof:


10. The method of claim 9, wherein each R is optionally substituted C₁₋₆ alkyl.
 11. The method of claim 9 or 10, wherein at least one of P₁ and P₂ is a hydroxyl protecting group.
 12. The method of any one of claims 9 to 11, wherein both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal.
 13. The method of any one of claims 9 to 12, wherein P₄ is a hydroxyl protecting group.
 14. The method of any one of claims 8 to 13, wherein said organic base is DBU or triethylamine.
 15. The method of any one of claims 8 to 14, wherein said Lewis acid is a salt of Li or Zn.
 16. The method of claim 2, wherein said non-macrocyclic intermediate is a compound of formula (IIIA) or a salt thereof:

wherein R₁ is H or a hydroxyl protecting group, and R₂ and R₃ combine to form a double bond; or (ii) R₁ and R₂ combine to form a bond, and R₃ is H; X₃ is oxo, or X₃ combines with the carbon atom to which it is attached to form a ketal, a thioketal, or —(CH(OP₅))—, wherein P₅ is H or a hydroxyl protecting group; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; P₄ is H or a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; and wherein said intermediate in the synthesis of eribulin is a compound of formula (IIIB) or a salt thereof:


17. The method of claim 16, wherein P₄ is a hydroxyl protecting group.
 18. The method of claim 16 or 17, wherein both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal.
 19. The method of any one of claims 16 to 18, wherein at least one of P₁ and P₂ is a hydroxyl protecting group.
 20. The method of any one of claims 16 to 19, wherein X₃ combines with the carbon atom to which it is attached to form —(CH(OP₅))—.
 21. The method of any one of claims 16 to 20, wherein R₁ and R₂ combine to form a bond, and R₃ is H.
 22. The method of any one of claims 2-7 and 16-21, wherein said olefin metathesis catalyst is a ruthenium-carbene complex.
 23. The method of claim 1, wherein said performing said macrocyclization reaction comprises contacting said non-macrocyclic intermediate with a Cr(II) salt and a Ni(II) salt.
 24. The method of claim 23, wherein said non-macrocyclic intermediate is a compound of formula (IVA) or a salt thereof:

wherein Y is iodide, bromide, or trifluoromethanesulfonate; a designates R stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or a designates S stereogenic center, and Z is OR₁, wherein R₁ is a hydroxyl protecting group; (i) R₂ is H or a hydroxyl protecting group, and R₃ and R₄ combine to form a double bond; or R₂ and R₃ combine to form a bond, and R₄ is H; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; and wherein said intermediate in the synthesis of eribulin is a compound of formula (IVB) or a salt thereof:

wherein a designates R stereogenic center, b designates S stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or a designates S stereogenic center, b designates R stereogenic center, and Z is OR₁, wherein R₁ is a hydroxyl protecting group.
 25. The method of claim 24, wherein Y is bromide.
 26. The method of claim 24 or 25, wherein R₂ and R₃ combine to form a bond, and R₄ is H.
 27. The method of any one of claims 24 to 26, wherein both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal.
 28. The method of any one of claims 24 to 26, wherein at least one of P₁ and P₂ is a hydroxyl protecting group.
 29. The method of any one of claims 24 to 28, wherein Z is a sulfonate.
 30. The method of any one of claims 24 to 28, wherein Z is OR₁, wherein R₁ is a hydroxyl protecting group.
 31. The method of claim 30, wherein Z is an ester, carbonate, or carbamate.
 32. The method of claim 1, wherein said performing said macrocyclization reaction comprises contacting said non-macrocyclic intermediate with a base.
 33. The method of claim 32, wherein said non-macrocyclic intermediate is a compound of formula (VA) or a salt thereof:

wherein Y is SO₂R₁, or COOR₁, wherein, when Y is SO₂R₁, R₁ is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COOR₁, R₁ is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo, or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; R₂ is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted aryl; and X is O, and each of P₁ and P₂ is independently a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; and wherein said intermediate in the synthesis of eribulin is a compound of formula (VB) or a salt thereof:

wherein (i) R₃ is H, R₄ is C₁₋₆ alkyl ether, and R₅ is H; (ii) R₅ is H, and R₃ and R₄ combine to form a double bond; or (iii) R₃ is H, and R₄ and R₅ combine to form a bond.
 34. The method of claim 33, wherein Y is SO₂R₁.
 35. The method of claim 33 or 34, wherein R₁ is optionally substituted aryl.
 36. The method of any one of claims 33 to 35, wherein both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal.
 37. The method of any one of claims 33 to 36, wherein R₂ is optionally substituted C₁₋₆ alkyl.
 38. The method of any one of claims 33 to 37, wherein R₃ is H, and R₄ and R₅ combine to form a bond.
 39. The method of any one of claims 32 to 38, wherein said base is a tertiary C₄₋₆ alkoxide.
 40. The method of claim 23, wherein said non-macrocyclic intermediate is a compound of formula (VIA) or a salt thereof:

wherein Y is iodide, bromide, or trifluoromethanesulfonate; (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine to form a double bond, each P₃ is independently H or a hydroxyl protecting group, and X₂, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR₆))—, wherein R₆ is H or a hydroxyl protecting group; or (a2) R₃ and R₄ combine to form a bond, R₅ is H, and each P₃ is independently H or a hydroxyl protecting group, and X₂, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR₆))—; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to form a bond; or (b2) Z and R₂ combine to form a double bond, and R₁ is a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; and wherein said intermediate in the synthesis of eribulin is a compound of formula (VIB) or a salt thereof:

wherein P₄ is H or a hydroxyl protecting group.
 41. The method of claim 40, wherein Z is iodide.
 42. The method of claim 40 or 41, wherein Y is trifluoromethanesulfonate.
 43. The method of any one of claims 40 to 42, wherein R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine to form a double bond, each P₃ is independently H or a hydroxyl protecting group, and X₂, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR₆))—, wherein R₆ is H or a hydroxyl protecting group.
 44. The method of any one of claims 40 to 43, wherein at least one of R₁, P₁, P₂, P₃, and P₄ is a hydroxyl protecting group.
 45. The method of any one of claims 40 to 43, wherein Z is chloride, bromide, or iodide, and R₁ and R₂ combine to form a bond.
 46. The method of any one of claims 3-7, 9-13, 16-21, 24-31, 33-38, and 40-45, wherein X is O.
 47. The method of any one of claims 3-7, 9-13, 16-21, 24-31, 33-38, and 40-45, wherein X is N.
 48. The method of claim 47, wherein X and P₂ combine to form optionally masked amino.
 49. A method of preparing:

said method comprising: (A) producing a compound of formula (IB) from a compound of formula (IA), the compound of formula (IA) having the following structure:

wherein R₁ is H or —CH₂X₁CH₂CH═CH₂, wherein X₁ is O, —P(P₉)₂—, or NP₅, and wherein each R₉ is independently H or —COOR₁₀, P₅ is an N-protecting group, and R₁₀ is C₁₋₆ alkyl; (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl ether, and R₄ is H; (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄ combine to form a double bond; or (a3) R₂ and R₃ combine to form a bond, and R₄ is H; (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇ combine to form a double bond; or (b2) R₅ and R₆ combine to form a bond, and R₇ is H; (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group; or (c2) R₈ and P₄ combine to form a double bond; each P₃ is independently H or a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; the compound of formula (IB) having the following structure:

(B) producing a compound of formula (IC) from the compound of formula (IB), the compound of formula (IC) having the following structure:

(C) producing a compound of formula (ID) from the compound of formula (IC), the compound of formula (ID) having the following structure:

wherein each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; and (D) producing eribulin or eribulin mesylate from the compound of formula (ID).
 50. The method of claim 49, wherein said producing said compound of formula (IB) comprises reacting the compound of formula (IA) with an olefin metathesis catalyst.
 51. The method of claim 49 or 50, wherein said producing said compound of formula (IC) comprises oxidizing the compound of formula (IB), wherein, in the compound of formula (IB), R₈ is H, and P₄ is H.
 52. The method of any one of claims 49 to 51, wherein said producing the compound of formula (ID) comprises reacting the compound of formula (IC) with a 1,4-reducing agent.
 53. The method of claim 52, wherein said producing the compound of formula (ID) further comprises reacting with a hydroxyl protecting group removing agent after said reacting the compound of formula (IC) with said 1,4-reducing agent.
 54. The method of any one of claim 53, wherein, in the compound of formula (ID), X is O, and P₂ is H.
 55. A method of preparing:

said method comprising: (A) producing a compound of formula (IIB) from a compound of formula (IIA) or a salt thereof:

wherein each R is independently optionally substituted alkyl or optionally substituted aryl; (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃ combine to form a double bond; or (ii) R₁ and R₂ combine to form a bond, and R₃ is H; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; P₄ is H or a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; and the compound of formula (IIB) having the following structure:

(B) producing a compound of formula (ID) from the compound of formula (IIB), the compound of formula (ID) having the following structure:

and (C) producing eribulin or eribulin mesylate from the compound of formula (ID).
 56. The method of claim 55, wherein the compound of formula (IIB) is produced by reacting the compound of formula (IIA) with an organic base and a Lewis acid.
 57. The method of claim 55 or 56, wherein producing said compound of formula (ID) comprises reacting the compound of formula (IIB) with a hydroxyl protecting group removing agent.
 58. The method of any one of claims 55 to 57, wherein both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal.
 59. A method of preparing:

said method comprising: (A) producing a compound of formula (IIIB) from the compound of formula (IIIA), the compound of formula (IIIA) having the following structure:

wherein (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃ combine to form a double bond; or (ii) R₁ and R₂ combine to form a bond, and R₃ is H; X₃ is oxo, or X₃ combines with the carbon atom to which it is attached to form a ketal, a thioketal, or —(CH(OP₅))—, wherein P₅ is H or a hydroxyl protecting group; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; P₄ is H or a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; the compound of formula (IIIB) having the following structure:

(B) producing a compound of formula (ID) from the compound of formula (IIIB), the compound of formula (ID) having the following structure:

and (C) producing eribulin or eribulin mesylate from the compound of formula (ID).
 60. The method of claim 59, wherein said producing the compound of formula (IIIB) comprises reacting the compound of formula (IIIA) with an olefin metathesis catalyst.
 61. The method of claim 59 or 60, wherein said producing said compound of formula (ID), comprises oxidizing the compound of formula (IIIB), wherein, in the compound of formula (IIIB), X₃, together with the carbon to which it is attached, forms —(CH(OP₅))—, wherein P₅ is H.
 62. The method of any one of claims 59 to 61, wherein said producing said compound of formula (ID), comprises oxidizing the compound of formula (IIIB), wherein, in the compound of formula (IIIB), P₄ is a hydroxyl protecting group, and R₄ and R₅ combine to form a double bond.
 63. A method of preparing

said method comprising: (A) producing a compound of formula (IVB) from a compound of formula (IVA), the compound of formula (IVA) having the following structure:

wherein Y is iodide, bromide, or trifluoromethanesulfonate; a designates R stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or a designates S stereogenic center, and Z is OR₁, wherein R₁ is a hydroxyl protecting group; (i) R₂ is H or a hydroxyl protecting group, and R₃ and R₄ combine to form a double bond; or (ii) R₂ and R₃ combine to form a bond, and R₄ is H; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; the compound of formula (IVB) having the following structure:

wherein a designates R stereogenic center, b designates S stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or a designates S stereogenic center, b designates R stereogenic center, and Z is OR₁, wherein R₁ is a hydroxyl protecting group; (B) producing a compound of formula (ID) from the compound of formula (IVB), the compound of formula (ID) having the following structure:

and (C) producing eribulin or eribulin mesylate from the compound of formula (ID).
 64. The method of formula 63, wherein said producing said compound of formula (IVB) comprises reacting the compound of formula (IVA) with a Cr(II) salt and a Ni(II) salt.
 65. The method of claim 63 or 64, wherein said producing said compound of formula (ID) comprises the step of nucleophilic ring-closing of the compound of formula (IVB).
 66. A method of preparing:

said method comprising: (A) producing a compound of formula (VB) from a compound of formula (VA):

wherein Y is SO₂R₁, or COOR₁, wherein, when Y is SO₂R₁, R₁ is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COOR₁, R₁ is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo, or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; R₂ is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted aryl; and X is O, and each of P₁ and P₂ is independently a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which is each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; the compound of formula (VB) having the following structure:

wherein (i) R₃ is H, R₄ is ether, and R₅ is H; (ii) R₅ is H, and R₃ and R₄, together with the bond connecting the atoms to which each is attached, combine to form a double bond; or (iii) R₃ is H, and R₄ and R₅ combine to form a bond; (B) producing a compound of formula (ID) from the compound of formula (VB), the compound of formula (ID) having the following structure:

and (C) producing eribulin or eribulin mesylate from the compound of formula (ID).
 67. The method of claim 66, wherein said producing said compound of formula (VB) comprises reacting the compound of formula (VA) with a base.
 68. The method of claim 66 or 67, wherein said producing said compound of formula (ID) comprises reacting the compound of formula (VB) with an electron-transferring reducing agent; and wherein Y is SO₂R₁, and R₁ is optionally substituted aryl.
 69. The method of any one of claims 66 to 68, wherein, in the compound of formula (VB), R₃ is H, and R₄ and R₅ combine to form a bond.
 70. A method of preparing:

said method comprising: (A) producing a compound of formula (VIB) from a compound of formula (VIA), the compound of formula (VIA) having the following structure:

wherein Y is iodide, bromide, or trifluoromethanesulfonate; (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine to form a double bond, each P₃ is independently H or a hydroxyl protecting group, and X₂, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR₆))—, wherein R₆ is H or a hydroxyl protecting group; or (a2) R₃ and R₄ combine to form a bond, R₅ is H, and each P₃ is independently H or a hydroxyl protecting group, and X₂, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR₆))—; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to form a bond; or (b2) Z and R₂ combine to form a double bond, and R₁ is H or a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; and the compound of formula (VIB) having the following structure:

wherein P₄ is H or a hydroxyl protecting group; (B) producing a compound of formula (VIC) from the compound of formula (VIB), the compound of formula (VIC) having the following structure:

(C) producing a compound of formula (ID) from the compound of formula (VIC), the compound of formula (ID) having the following structure:

and (D) producing eribulin or eribulin mesylate from the compound of formula (ID).
 71. The method of claim 70, wherein said producing said compound of formula (VIB) comprises reacting the compound of formula (VIA) with a Cr(II) salt and a Ni(II) salt.
 72. The method of claim 70 or 71, wherein said producing said compound of formula (ID) comprises reacting the compound of formula (VIB) with a hydroxyl protecting group removing agent.
 73. The method of any one of claims 49 to 72, wherein, in the compound of formula (ID), both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal.
 74. The method of any one of claims 49 to 73, wherein, in the compound of formula (ID), P₁ is H.
 75. The method of any one of claims 49 to 74, wherein, in the compound of formula (ID), X is O, and P₂ is H.
 76. The method of claim 75, wherein said producing eribulin or eribulin mesylate from the compound of formula (ID) comprises aminating the compound of formula (ID).
 77. The method of any one of claims 49 to 74, wherein, in the compound of formula (ID), X and P₂ combine to form a masked amino.
 78. The method of claim 77, wherein said producing eribulin or eribulin mesylate from the compound of formula (ID) comprises reacting the compound of formula (ID) with an amino unmasking agent.
 79. The method of any one of claims 49 to 78, wherein eribulin mesylate is produced by salifying eribulin with methanesulfonic acid.
 80. A method of preparing an intermediate in the synthesis of eribulin, said method comprising performing a Prins reaction by contacting a compound of formula (VIIA) with a compound of formula (VIIB) and R₃OH, wherein R₃ is an optionally substituted acyl; wherein the compound of formula (VIIA) has the following structure:

wherein Y₁ is SO₂R₁ or COOR₁, and R₁ is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; X₁ is O, or X₁, together with the carbon to which it is attached, forms a cyclic acetal; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl; wherein the compound of formula (VIIB) has the following structure:

wherein P₃ is H or a hydroxyl protecting group; each P₄ is independently a hydroxyl protecting group, or both P₄ groups, together with the atoms to which each is attached, combine to form a cyclic protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, wherein X₂ is O, —CH₂—, or NP₅, wherein P₅ is sulfonyl; and wherein said intermediate is a compound of formula (VIIC):


81. The method of claim 80, wherein said performing a Prins reaction comprises reacting the compound of formula (VIIA) with a Lewis acid.
 82. A method of preparing an intermediate in the synthesis of eribulin, said method comprising: (A) cleaving the double bond in a compound of formula (VIIIA) to afford a compound of formula (VIIIB), the compound of formula (VIIIA) having the structure:

wherein X₁ is oxo, or X₁, together with the carbon atom to which it is attached, forms a ketal or —(CH(OP₃))—, wherein P₃ is H or a hydroxyl protecting group; R₁ is H or —CH₂OP₄; each of P₁, P₂, and P₄ is independently a hydroxyl protecting group, or P₁ and P₄, together with the atoms to which each is attached, combine to form a cyclic protected diol; and the compound of formula (VIIIB) having the structure:

(B) reacting the compound of formula (VIIIB) with a compound of formula (VIIIB-a) to afford a compound of formula (VIIIC):

wherein R₂ is H or —CH₂CH₂OP₅, and P₅ is a hydroxyl protecting group; and the compound of formula (VIIIB-a) has the following structure:

(C) reacting the compound of formula (VIIIC) with a dehydrating agent to afford a compound of formula (VIIID):

(D) reacting the compound of formula (VIIID) with a dihydroxylating agent to afford a compound of formula (VIIIE):

(E) preparing a compound of formula (VIIIF) through a reaction sequence comprising reacting the compound of formula (VIIIE) with N-bromosuccinimide to afford a first intermediate, reacting said first intermediate with an acylating agent to afford a second intermediate, and (a), when R₂ is —CH₂CH₂OP₅, contacting said second intermediate with a reducing agent, or (b), when R₂ is H, allylating said second intermediate compound of formula (VIIIF):

wherein Z is an ester or —OP₇, wherein P₇ is H or a hydroxyl protecting group, and R₃ is —CH₂CH₂OP₅ or —CH₂CH═CH₂; (F) reacting the compound of formula (VIIIF) with a 1,4-reducing agent to afford a compound of formula (VIIIG):

and (G) forming a compound of formula (VIIIH) through a reaction sequence comprising reacting the compound of formula (VIIIG) with a Brønsted acid and Y—H, wherein Y is optionally substituted C₁₋₆ alkyl, the compound of formula (VIIIH) having the following structure:

wherein Y is optionally substituted C₁₋₆ alkyl ether; R₂ is —CH₂CH₂OP₅; X₂ is oxo, or X₂, together with the carbon to which it is attached, forms a ketal or —(CH(OP₆))—, wherein P₆ is a hydroxyl protecting group.
 83. The method of claim 82 further comprising: (H) replacing P₂ in the compound of formula (VIIIH) with —Si(R₄)₂H to afford a compound of formula (VIIIJ):

wherein each R₄ is independently optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; (I) reacting the compound of formula (VIIIJ) with a Lewis acid to afford a compound of formula (VIIIK):

wherein Y₂ is fluoro, chloro, or bromo; and (J) reacting the compound of formula (VIIIK) with a hydroxyl protecting group removing agent and then reacting with a hydroxyl protecting agent to afford a compound of formula (VIIIL):

wherein P₂ is a hydroxyl protecting group.
 84. A compound of formula (IA) or (IB):

or a salt thereof, wherein R₁ is H or —CH₂X₁CH₂CH═CH₂, wherein X₁ is O, —O(R₉)₂—, or NP₅, and wherein each R₉ is independently H or —COOR₁₀, P₅ is an N-protecting group, and R₁₀ is C₁₋₆ alkyl; (a1) R₂ is H or a hydroxyl protecting group, R₃ is C₁₋₆ alkyl ether, and R₄ is H; (a2) R₂ is H or a hydroxyl protecting group, and R₃ and R₄ combine to form a double bond; or (a3) R₂ and R₃ combine to form a bond, and R₄ is H; (b1) R₅ is H or a hydroxyl protecting group, and R₆ and R₇ combine to form a double bond; or (b2) R₅ and R₆ combine to form a bond, and R₇ is H; (c1) R₈ is H, and P₄ is H or a hydroxyl protecting group; or (c2) R₈ and P₄ combine to form a double bond; each P₃ is independently H or a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl.
 85. A compound of formula (IC):

or a salt thereof, wherein each P₃ is independently a hydroxyl protecting group; and X is O, P₁ is a hydroxyl protecting group, and P₂ is H or a hydroxyl protecting group; or P₁ is a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino.
 86. A compound of formula (IIA) or (IIB):

or a salt thereof, wherein each R is independently optionally substituted alkyl or optionally substituted aryl; (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃ combine to form a double bond; or (ii) R₁ and R₂ combine to form a bond, and R₃ is H; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; P₄ is H or a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl.
 87. A compound of formula (IIIA) or (IIIB):

or a salt thereof, wherein (i) R₁ is H or a hydroxyl protecting group, and R₂ and R₃ combine to form a double bond; or (ii) R₁ and R₂ combine to form a bond, and R₃ is H; X₃ is oxo, or X₃ combines with the carbon atom to which it is attached to form a ketal, a thioketal, or —(CH(OP₅))—, wherein P₅ is H or a hydroxyl protecting group; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; P₄ is H or a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl.
 88. A compound of formula (IVA) or (IVB):

or a salt thereof, wherein Y is iodide, bromide, or trifluoromethanesulfonate; (a1) a designates R stereogenic center, b designates S stereogenic center, and Z is a sulfonate, chloride, bromide, or iodide; or (a2) a designates S stereogenic center, b designates R stereogenic center, and Z is OR₁, wherein R₁ is a hydroxyl protecting group; (b1) R₂ is H or a hydroxyl protecting group, and R₃ and R₄ combine to form a double bond; or (b2) R₂ and R₃ combine to form a bond, and R₄ is H; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl
 89. A compound of formula (VA) or (VB):

or a salt thereof, wherein Y is SO₂R₁ or COOR₁, wherein, when Y is SO₂R₁, R₁ is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COOR₁, R₁ is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo, or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; R₂ is optionally substituted alkyl, optionally substituted arylalkyl, or optionally substituted aryl; and X is O, and each of P₁ and P₂ is independently a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which is each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl.
 90. A compound of formula (VIA) or (VIB):

or a salt thereof, wherein Y is iodide, bromide, or trifluoromethanesulfonate; P₄ is H or a hydroxyl protecting group; (a1) R₃ is H or a hydroxyl protecting group, R₄ and R₅ combine to form a double bond, each P₃ is independently H or a hydroxyl protecting group, and X₂, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR₆))—, wherein R₆ is H or a hydroxyl protecting group; or (a2) R₃ and R₄ combine to form a bond, R₅ is H, and each P₃ is independently H or a hydroxyl protecting group, and X₂, together with the carbon to which it is attached, forms a carbonyl or —(CH(OR₆))—; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; (b1) Z is chloride, bromide, or iodide, and R₁ and R₂ combine to form a bond; or (b2) Z and R₂ combine to form a double bond, and R₁ is a hydroxyl protecting group; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl.
 91. A compound of formula (VIC):

or a salt thereof, wherein a designates R stereogenic center or S stereogenic center; Y₁ is SO₂R₁, or COOR₁, and R₁ is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl;

wherein P₃ is H or a hydroxyl protecting group; each P₄ is independently a hydroxyl protecting group, or both P₄ groups, together with the atoms to which each is attached, combine to form a cyclic protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, wherein X₂ is O, —CH₂—, or NP₅, wherein P₅ is sulfonyl; R₃ is an optionally substituted acyl; and X is O, and each of P₁ and P₂ is independently H or a hydroxyl protecting group, or P₁ and P₂, together with the atoms to which each is attached, combine to form a cyclic protected diol; or X is N, and P₁ is H or a hydroxyl protecting group, and X and P₂ combine to form optionally masked amino; or P₁ and P₂, together with the atoms to which each is attached, combine to form an aminal or 1,3-oxazolidin-2-one-5-yl.
 92. A compound of formula (VIIB):

where P₃ is a hydroxyl protecting group; each P₄ is independently a hydroxyl protecting group, or both P₄ groups, together with the atoms to which each is attached, combine to form a cyclic protected diol; and R₄ is H or —CH₂X₂CH₂CH═CH₂, where X₂ is O, —CH₂—, or NP₅, where P₅ is sulfonyl.
 93. A compound of formula (IVE):

wherein Y is iodide, bromide, or trifluoromethanesulfonate; Z is an ester, a sulfonate, chloride, bromide, or iodide; each P₃ is independently H or a hydroxyl protecting group, and X₂ is oxo; or both P₃ groups and X₂, together with the atoms to which each is attached, combine to form ketal; and (a1) R₂ is H or a hydroxyl protecting group, R₃ and R₄ combine to form a double bond; or (a2) R₂ and R₃ combine to form a bond, and R₄ is H; (b1) R₇ and R₈ combine to form a bond, and R₉ is H; or (b2) R₇ is H or a hydroxyl protecting group, and R₈ and R₉ combine to form a double bond; (c1) X₃ is oxo and R₁₀ is H or —OP₅, where P₅ is H or an ether hydroxyl protecting group; or (c2) X₃ and R₁₀ together with the carbon atom to which they are attached form —CH₂OP₆, wherein P₆ is H or a hydroxyl protecting group, and R₁₀ is H. 